Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues
Open accessAbstract
Lysine acetyltransferases (KATs) cooperate with oncogenes such as c-Myc, estrogen receptor, and lysine methyltransferase 2A (KMT2A) fusions to sustain malignant programs. Targeting of KAT proteins has shown clinical efficacy; however, achieving homolog selectivity for most KATs remains a major challenge. By extending cereblon (CRBN)-based molecular glues beyond the canonical degron space, we developed an exquisitely selective degrader of KAT2A. Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Selective KAT2A degradation leads to potent ablation of histone H3 lysine 9 acetylation (H3K9Ac), antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model, establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies. More generally, degron-independent recruitment extends the CRBN-targetable proteome.
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Claims the paper makes
10 of 21 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured
- Premisecitation
KAT2A lacks a canonical G-loop motif or a similar structure.
“Based on prior structures and AlphaFold2 (39) predictions, KAT2A lacked a canonical G-loop motif or a similar structure, which suggested a different binding mode.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [39] source
- Findingown data
KAT2ANTD buries a substantial portion of both CRBNNTD and CRBNCTD, forming a broad PPI distinct from the more hotspot-driven interfaces of G-loop neo-substrates, the G-loop mimetic, and the non-G-loop G3BP2.
“We found that KAT2ANTD buries a substantial portion of both the CRBNNTD and CRBNCTD, forming a broad PPI that is distinct from the more hotspot-driven interfaces created by the G-loop neo-substrates (e.g., IKZF1(45), GSPT1(40)), the G-loop mimetic (VAV1(11)), and the non-G-loop (G3BP2(14)) (Fig 3F).”
Quote in the paperSubstantial claim1 of 3 sources checked - Premisecitation
KAT2A was previously identified as a potential targetable dependency in AML through functional genomic studies.
“KAT2A has previously been identified as a potential targetable dependency in AML through functional genomic studies (28, 27, 46).”
Quote in the paperNot a substantial claim3 of 3 sources checked - Premisecitation
The same CRBN loop 146-153 also plays a role in G3BP2 recruitment.
“the same CRBN loop (146-153) also plays a role in G3BP2 recruitment (14).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] source
- Premisecitation
The G3BP2 interaction with CRBN appears more hotspot-driven, engaging a defined interface on the LON domain that mimics a natural PPI.
“In contrast to KAT2A, however, the interaction of G3BP2 with CRBN appears more hotspot-driven, engaging a defined interface on the LON domain that the authors describe as mimicking a natural PPI.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] source
- Findingown data
The Loop interface is formed between F150 on the CRBN N-terminal domain loop and several residues near the binuclear zinc-coordinating region of KAT2ANTD.
“The third interface, the “Loop interface”, is formed between F150 on the N-terminal domain loop of CRBN (CRBNNTD) and several residues near the binuclear zinc-coordinating region of KAT2ANTD (Fig. 3D).”
Quote in the paperNot a substantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
- Findingown data
Compound 1 was identified as a strong degrader of KAT2A from the authors' database.
“We identified compound (1) as a strong degrader of KAT2A (Fig. 1A–B, fig. S1A).”
Quote in the paperSubstantial claim- Rests on an assumption: The internal degradation proteomics database is comprehensive enough to identify KAT2A-targeting molecular glues.
- Findingown data
At the compound-mediated interface, the bulky hydrophobic groups of 4 wrap around surface-exposed Y200 within an α-helix of KAT2ANTD.
“At the compound-mediated interface, the bulky hydrophobic groups of 4 wrap around the surface exposed Y200 within an α-helix of KAT2ANTD (Fig. 3A).”
Quote in the paperSubstantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
- Findingown data
The overall arrangement is stabilized by three distinct interaction sites between KAT2ANTD and CRBN.
“The overall arrangement is stabilized by three distinct interaction sites between KAT2ANTD and CRBN (Fig. 3A–D).”
Quote in the paperSubstantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
- Findingown data
In mice engrafted with MV4;11 cells, a pharmacodynamics experiment showed KAT2A degradation and loss of H3K9Ac in harvested CD45+ cells after three once-daily 20 mg/kg doses of compound 4.
“a pharmacodynamics experiment using mice engrafted with MV4;11 cells and treated with a dose range of 4 showed KAT2A degradation and loss of H3K9Ac in harvested CD45+ cells after three doses once-daily 20 mg/kg of 4 (Fig. S5B).”
Quote in the paperSubstantial claim - Findingown data
The Y200A mutation significantly perturbed wild-type KAT2ANTD recruitment to CRBN, with a 25-fold IC50 shift.
“Using a TR-FRET displacement assay we found that Y200A mutation is sufficient to significantly perturb WT KAT2ANTD recruitment to CRBN (25x IC50 shift; Fig. 3E).”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
- Findingown data
Compound 4 treatment reduced H3K9Ac in a neddylation- and proteasome-dependent manner in EOL-1 and MV4;11 cells.
“4 treatment also showed a clear reduction of H3K9Ac in a neddylation- and proteasome-dependent manner in both cell lines (Fig. 4D)”
Quote in the paperSubstantial claim - Findingown data
The Y200A mutation and mutations in the Loop and Helix interfaces disrupted 4-induced KAT2A ubiquitylation.
“Further validation using in vitro ubiquitylation assays show that the Y200A mutation as well as mutations on the Loop and Helix interfaces are sufficient to disrupt 4 induced KAT2A ubiquitylation (fig. S4F).”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
- Findingown data
Compound 4 recruits KAT2ANTD through a globular helical domain mediated by a solvent-exposed tyrosine interacting with 4.
“Instead, 4 recruits KAT2ANTD via a globular helical domain mediated by a solvent-exposed tyrosine interacting with 4.”
Quote in the paperSubstantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
- Findingown data
Global expression proteomics in EOL-1 and MV4;11 after 6-hour treatment with 1 μM compound 4 showed KAT2A as the only protein substantially degraded in both cell lines.
“we profiled the degradation activity of 4 by global expression proteomics in EOL-1 and MV4;11 after a 6-hour treatment with 1 μM of 4 and found that KAT2A is the only protein substantially degraded in both cell lines (Fig 4B, C)”
Quote in the paperSubstantial claim- Rests on an assumption: The proteomic assays used can detect all functionally relevant off-target degradation by compound 4.
- Findingown data
Global proteomics and CRBN-IP proteomics identified KAT2A as the only protein robustly recruited to CRBN and degraded in the presence of compound 4.
“we validated proteome-wide selectivity by performing both global proteomics (Fig. 2D) and CRBN-IP-based proteomics from Kelly cell lysate (Fig. 2E) and identified KAT2A as the only protein robustly recruited to CRBN and degraded in the presence of 4”
Quote in the paperSubstantial claim- Rests on an assumption: The proteomic assays used can detect all functionally relevant off-target degradation by compound 4.
- Findingown data
A 2.9 Å cryo-EM structure of the DDB1ΔB-CRBN-4-KAT2ANTD ternary complex was determined.
“we determined a 2.9 Å resolution cryo-EM structure of the DDB1ΔB-CRBN-4-KAT2ANTD ternary complex (Fig. 3, fig. S3).”
Quote in the paperSubstantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
- Findingown data
Compound 4 significantly reduced H3K9Ac in a dose-dependent manner in Kelly cells.
“Furthermore, 4 significantly reduced histone H3 lysine 9 acetylation (H3K9Ac), a primary KAT2A acetylation target (42), in a dose-dependent manner in Kelly cells (Fig. 2C).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] source
- Findingown data
In an in vitro reconstituted CRL4CRBN system, compound-dependent ubiquitylation of full-length KAT2A was observed.
“we used an in vitro reconstituted system with recombinant CRL4CRBN E3 ubiquitin ligase and observed compound-dependent ubiquitylation of full-length KAT2A (Fig. 1E, lanes 1-2)”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
- Findingown data
The Helix interface is formed between the end of two α-helixes on KAT2ANTD and the zinc-coordinating region on CRBNCTD.
“The second interface, the “Helix interface”, is formed between the end of two α-helixes on KAT2ANTD and the zinc-coordinating region on the C-terminal domain of CRBN (CRBNCTD) (Fig. 3C).”
Quote in the paperSubstantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
- Findingown data
Compound 1 was the only compound in the entire database that induced KAT2A degradation.
“1 was the only compound across the entire database to induce degradation of KAT2A (fig. S1A, B).”
Quote in the paperSubstantial claim- Rests on an assumption: The internal degradation proteomics database is comprehensive enough to identify KAT2A-targeting molecular glues.
- Findingown data
Compound 1 did not degrade KAT2B, a close homolog of KAT2A.
“1 does not display any degradation activity against KAT2B, a close homolog of KAT2A (Fig. 1D).”
Quote in the paperSubstantial claim - Findingown data
Mutating multiple key residues in the Loop and Helix interfaces completely ablated recruitment.
“Moreover, mutating multiple key residues in the Loop (F109E, F202E, F183A, R206A) and Helix (K289A, V285A, R277A) interfaces, were sufficient to completely ablate recruitment (Fig. 3E).”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
- Findingown data
A KAT2A-selective degrader was created by moving CRBN molecular glues past the usual degron region.
“By extending CRBN-based molecular glues beyond the canonical degron space, we develop an exquisitely selective degrader of KAT2A.”
Quote in the paperSubstantial claim - Interpretationown data
Selective KAT2A degradation by a molecular glue degrader exhibits context-specific anti-leukemic activity rather than general cytotoxicity.
“These results demonstrate that the selective degradation of KAT2A by an MG degrader exhibits context-specific anti-leukemic activity rather than general cytotoxicity.”
Quote in the paperSubstantial claim - Interpretationown data
KAT2A degradation demonstrates anti-leukemia activity in vivo.
“We conclude that KAT2A degradation demonstrates anti-leukemia activity in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: The DFAM-68555 patient-derived xenograft model's response to compound 4 predicts clinical anti-leukemic benefit in human KMT2A::MLLT3 AML.
- Interpretationreasoning
The distinctive KAT2A binding mode suggests a major expansion of the potential target space for CRBN-mediated degradation.
“The distinctive nature of the KAT2A binding mode, essentially consisting of a single exposed residue within an α-helix, the extensive protein-protein interaction (PPI) interface area with CRBN supporting this interaction, and the dissimilarity with the canonical IMiD degrons, together suggest a major expansion of the potential target space for CRBN-mediated degradation.”
Quote in the paperSubstantial claim - Interpretationreasoning
The extensive interactions defining 4-mediated KAT2A recruitment explain the selectivity for KAT2A over KAT2B despite the analogous tyrosine and 71% sequence identity.
“As such, although KAT2BNTD has a tyrosine analogous to Y200 in KAT2A, and 71% sequence identity, the extensive nature of interactions that define 4-mediated KAT2A recruitment to CRBN explains the exquisite selectivity for KAT2A over KAT2B.”
Quote in the paperSubstantial claim - Interpretationown data
Compound 1 acts as a direct molecular glue between CRBN and KAT2A.
“unambiguously confirming that 1 acts as a direct molecular glue between CRBN and KAT2A.”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
- Interpretationown data
The selectivity of the degraders is achieved through a composite surface area comprising both molecular-glue-mediated contacts and direct KAT2A-CRBN interfaces.
“The selectivity of our degraders is achieved through a composite surface area comprising both MG-mediated contacts and direct KAT2A-CRBN interfaces.”
Quote in the paperSubstantial claim - Interpretationreasoning
The large interface is likely necessary to compensate for the lack of extensive primary interactions between the compound/CRBN composite surface and KAT2A.
“This large interface is likely necessary to compensate for the lack of extensive primary interactions between the compound/CRBN composite surface and KAT2A.”
Quote in the paperSubstantial claim - Premisecitation
Recent public disclosures reported additional non-G-loop targets, including CCNE1, ARNT, CDK2, and ALK.
“Recent public disclosures by biotech companies have reported additional non G-loop targets, including CCNE1 (50), ARNT (51), CDK2 (52), ALK (53)”
Quote in the paperNot a substantial claim0 of 3 sources checked - Interpretationreasoning
The exceptional selectivity of compound 4 enabled the first pharmacologic testing of selective KAT2A degradation for AML treatment.
“From a translational perspective, the exceptional selectivity of 4 enabled the first pharmacologic testing of selective KAT2A degradation for the treatment of AML.”
Quote in the paperSubstantial claim- Rests on an assumption: The DFAM-68555 patient-derived xenograft model's response to compound 4 predicts clinical anti-leukemic benefit in human KMT2A::MLLT3 AML.
- Interpretationown data
KAT2A is a targetable vulnerability for treating a wide range of malignancies.
“establishing KAT2A as a targetable vulnerability to treat a wide range of malignancies.”
Quote in the paperSubstantial claim- Rests on an assumption: The DFAM-68555 patient-derived xenograft model's response to compound 4 predicts clinical anti-leukemic benefit in human KMT2A::MLLT3 AML.
- Interpretationreasoning
CRBN-MG binary complexes should be viewed as key recognition elements reminiscent of the heavy chain CDR3 of immunoglobulins.
“Therefore, we propose that CRBN-MG binary complexes should be viewed as key recognition elements reminiscent of the heavy chain complementary-determining region (CDR) 3 of Ig’s (Fig. S4G).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Degron-independent recruitment extends the CRBN-targetable proteome.
“More generally, degron-independent recruitment extends the CRBN-targetable proteome.”
Quote in the paperSubstantial claim - Interpretationreasoning
The targetable universe of proteins degradable by CRBN-recruiting molecular glues is not limited to proteins containing the G-loop degron motif or its structural mimic.
“together these results show that the targetable universe of proteins degradable by CRBN-recruiting MGs is not limited to POIs that contain the G-loop degron motif (4), or its structural mimic (11).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data
Additional loops in CRBN, most notably residues 146-153, behave like CDR1 and CDR2 of immunoglobulins, accommodating the target while keeping entropic costs in check due to limited flexibility.
“Furthermore, additional loops in CRBN (most notably residues 146-153) behave like CDR1 and CDR2 of Ig’s, whereby they accommodate the target while keeping entropic costs in check due to their limited flexibility (Fig. S4G)”
Quote in the paperSubstantial claim
- May combine two claims. 24
- Classified as probably not a substantial claim. 1
May combine two claims.
PremisecitationThe recently reported G3BP2 degraders also lack a canonical degron, and their major interface contacting the molecular glue is a helix without noticeable degron-like features.
“The recently reported degraders of G3BP2 (14) also lack a canonical degron and, similar to KAT2A, the major interface contacting the MG is a helix without noticeable degron-like features.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] source
The Results section describes G3BP2 as a molecular-glue-induced CRBN neosubstrate and reports that its NTF2L domain lacks recognizable G-loop degrons or close surface matches to known degrons. It does not identify the major G3BP2 interface contacting the molecular glue as a helix; the prominent loop it describes belongs to CRBN, not G3BP2. Page numbers are unavailable in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataCompound 1 caused dose-dependent KAT2A degradation by western blot, and this degradation was rescued by MLN4924, bortezomib, and pomalidomide.
“orthogonally confirmed dose-dependent KAT2A degradation by western blot, and demonstrated that this degradation can be rescued by pre-treatment with a UBA3/NAE1 inhibitor, MLN4924 (37), a proteasome inhibitor, bortezomib (38), and a competing CRBN ligand, pomalidomide (7) (Fig. 1D).”
Quote in the paperSubstantial claim1 of 3 sources checkedMay combine two claims.
InterpretationcitationThe large interface involves extensive interactions between CRBN-MG and KAT2A, providing measurable affinity in the absence of MG and resembling immunoglobulin binding to antigens.
“Furthermore, the large interface area involves extensive interactions between CRBN-MG and KAT2A, providing measurable affinity of KAT2A-CRBN in the absence of MG (54) and resembling the molecular recognition seen in immunoglobulin (Ig) binding to antigens.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [54] source
The Results section, “Intrinsic affinity between CRBN and neo-substrates” (page unavailable), reports measurable binding of CRBN to IKZF1 and CK1α in the absence of a molecular glue. It does not report binding between CRBN and KAT2A or describe a CRBN–KAT2A interface; the immunoglobulin comparison is likewise not made for that pair. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataCompound 4 showed potent KAT2A degradation with no GSPT1 or GSPT2 degradation up to 1 μM and negligible KAT2B degradation at doses above 250 nM.
“By immunoblot, 4 showed potent KAT2A degradation with no GSPT1 or GSPT2 degradation activity up to 1 μM, and negligible KAT2B degradation at doses >250 nM (Fig. 2C).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn the DFAM-68555 PDX model, 20 mg/kg/day compound 4 significantly improved median survival versus vehicle (47.5 versus 36.5 days, p = 0.0023) and decreased leukemia burden in peripheral blood at several timepoints.
“The cohort randomized to 20 mg/kg/day treatment of 4 showed significantly improved median survival compared to those in the vehicle control cohort (47.5 days versus 36.5 days, p = 0.0023), as well as decreased leukemia burden in peripheral blood at several timepoints (Fig. 4F).”
Quote in the paperSubstantial claim- Rests on an assumption: The DFAM-68555 patient-derived xenograft model's response to compound 4 predicts clinical anti-leukemic benefit in human KMT2A::MLLT3 AML.
May combine two claims.
Findingown dataCompound 1 did not induce polyubiquitylation of the corresponding KAT2B N-terminal domain, establishing biochemical selectivity.
“We also found that 1 does not induce poly-ubiquitylation of the corresponding N-terminal domain of KAT2B (KAT2BNTD), establishing biochemical selectivity of this induced interaction (Fig 1E, lanes 9,10).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataImmunoblots of human CD45+ cells from bone marrow at death showed potent KAT2A degradation and loss of global H3K9Ac in the compound 4 treated cohort.
“Immunoblots in human CD45+ cells harvested from bone marrow samples at the time of death of each mouse in the survival experiment showed potent degradation of KAT2A and loss of global H3K9Ac levels in the 4 treated cohort (Fig. 4G).”
Quote in the paperSubstantial claim- Rests on an assumption: The DFAM-68555 patient-derived xenograft model's response to compound 4 predicts clinical anti-leukemic benefit in human KMT2A::MLLT3 AML.
May combine two claims.
Findingown dataCompound 2, with a 2-THP group replacing the isopropyl, ablated GSPT1 targeting while enhancing KAT2A-CRBN dimerization.
“demonstrated that a 2-tetrahydropyran (2-THP) group replacing the isopropyl ablates GSPT1 targeting, as exemplified in compound (2) (Fig. 2A, fig. S2B, C), while enhancing KAT2A-CRBN dimerization.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe structure showed clear density for each protein and unambiguous density for compound 4 at the CRBN-KAT2ANTD interface.
“The structure showed clear density for each protein and unambiguous density for 4 at the interface between CRBN and KAT2ANTD (Fig. 3, fig S4A, B, D).”
Quote in the paperSubstantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
May combine two claims.
Findingown dataOnly the N-terminal domain of KAT2A was polyubiquitylated in the presence of 1, indicating that the recruitment interface lies within KAT2ANTD.
“In vitro ubiquitylation assays using the individual domains showed that only the N-terminal domain was polyubiquitylated in the presence of 1, suggesting that the recruitment interface is located within the N-terminal domain of KAT2A (KAT2ANTD) (Fig. 1E, lanes 7,8).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSubcutaneous dosing of 20 mg/kg compound 4 was tolerated and resulted in acceptable exposure in peripheral blood.
“We found subcutaneous dosing of 20 mg/kg to be tolerated and to result in acceptable exposure in peripheral blood (fig. S5A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIP-MS with recombinant CRBN in Kelly cell lysates showed potent KAT2A enrichment in the presence of 1 and undesired GSPT1 activity.
“demonstrating potent enrichment of KAT2A in the presence of 1, as well as undesired activity against GSPT1 (Fig. 1C).”
Quote in the paperSubstantial claim- Rests on an assumption: The internal degradation proteomics database is comprehensive enough to identify KAT2A-targeting molecular glues.
May combine two claims.
Findingown dataThe ternary complex had high affinity, and weak but observable binding of KAT2A to CRBN occurred in the absence of glue.
“which was underscored by high ternary complex affinity and observable, albeit weak, binding of KAT2A to CRBN in the absence of glue (fig. S4H).”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
May combine two claims.
Findingown dataSequential modifications improved KAT2A degradation in cells, with compound 4 showing the most potent degradation in the series (Dmax 90%).
“we found that each sequential modification led to improved KAT2A degradation in cells, with 4 displaying the most potent KAT2A degradation in the series (Dmax: 90%, Fig. 2B).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationThe compound-mediated interface between CRBN and KAT2ANTD lacks a G-loop motif and does not contain the structural mimic seen in VAV1.
“The compound-mediated interface between CRBN and KAT2ANTD not only lacks a G-loop structural motif but also does not contain a structural mimic of the canonical motif as seen in VAV1 (11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] source
- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
May combine two claims.
Findingown dataThe mice showed no treatment-related changes in body weight or circulating blood cell counts.
“The mice showed no treatment-related changes in body weight or circulating blood cell counts (fig. S5C, D).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe KAT2A-binding site is located in its non-catalytic NTD, suggesting that molecular glues exploiting non-catalytic domains may offer improved selectivity.
“Furthermore, the KAT2A-binding site is located in its non-catalytic NTD, suggesting that MGs that exploit non-catalytic domains of POIs for recruitment may offer improved selectivity.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataEach of the three interaction sites contributes to an avid interface between CRBN and KAT2A and is indispensable for KAT2A recognition.
“This suggests that each of the three interaction sites contributes to an avid interface between CRBN and KAT2A and is indispensable for KAT2A recognition”
Quote in the paperSubstantial claim- Rests on an assumption: The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
May combine two claims.
Interpretationown dataCompound 4 is a potent molecular glue degrader of KAT2A with exquisite selectivity and no observable off-target degradation.
“Together, these data establish 4 as a potent molecular glue degrader of KAT2A, with exquisite selectivity and no observable off-target degradation.”
Quote in the paperSubstantial claim- Rests on an assumption: The proteomic assays used can detect all functionally relevant off-target degradation by compound 4.
May combine two claims.
Interpretationown dataCompound 1 mediates KAT2A degradation in a CRBN- and proteasome-dependent manner.
“Together, these data confirm that 1 mediates KAT2A degradation in a CRBN and proteasome-dependent manner.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCompound 4 recruits KAT2A to CRBN via a relatively featureless surface through a single exposed amino acid, Y200, on a helix, a structural feature without homology to previously reported degrons.
“4 recruits KAT2A to CRBN via a relatively featureless surface through a single exposed amino acid (Y200) located on a helix, a structural feature without homology to previously reported degrons.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningIn this model, binding of different MGs, not mutations, changes the properties of the binding interface and thereby dictates POI selectivity.
“In this model, binding of different MGs, not mutations, changes the properties of the binding interface, thereby dictating POI selectivity.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataCRBN recruits KAT2A independently of a degron, with the molecular glue engaging a surface-exposed tyrosine in an antibody-like recognition mode.
“Cryo-electron microscopy revealed that CRBN recruits KAT2A independently of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition.”
Quote in the paperSubstantial claim- Rests on an assumption: The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
Probably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningFurther diversifying substituents attached to the core glutarimide moiety of CRBN-recruiting MGs is likely to yield potent and selective leads for diverse POIs, including those lacking the G-loop degron.
“As such, further diversifying the substituents attached to the core glutarimide moiety of CRBN-recruiting MGs is likely to yield potent and selective leads for a diverse range of POIs, including those that lack the G-loop degron.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataSelective KAT2A degradation causes H3K9Ac ablation, antiproliferative effects in AML cell lines, and in vivo efficacy in a PDX model.
“Selective KAT2A degradation leads to potent ablation of H3K9Ac, antiproliferative effects in acute myeloid leukemia cell lines, and in vivo efficacy in a patient-derived xenograft model”
Quote in the paperSubstantial claim- Rests on an assumption: The DFAM-68555 patient-derived xenograft model's response to compound 4 predicts clinical anti-leukemic benefit in human KMT2A::MLLT3 AML.
The paper relies on this without support.
The DFAM-68555 patient-derived xenograft model's response to compound 4 predicts clinical anti-leukemic benefit in human KMT2A::MLLT3 AML.
“To assess in vivo efficacy, the DFAM-68555 (KMT2A::MLLT3 AML) PDX model was injected into the tail veins of immunodeficient mice.”
“We conclude that KAT2A degradation demonstrates anti-leukemia activity in vivo.”
The paper relies on this without support.
The proteomic assays used can detect all functionally relevant off-target degradation by compound 4.
“we validated proteome-wide selectivity by performing both global proteomics (Fig. 2D) and CRBN-IP-based proteomics from Kelly cell lysate (Fig. 2E) and identified KAT2A as the only protein robustly recruited to CRBN and degraded in the presence of 4”
“with exquisite selectivity and no observable off-target degradation.”
The paper relies on this without support.
The in vitro ubiquitylation and TR-FRET measurements faithfully report the cellular CRBN-KAT2A interaction.
“To validate KAT2A as a genuine CRBN-dependent neo-substrate, we used an in vitro reconstituted system with recombinant CRL4CRBN E3 ubiquitin ligase”
“This suggests that each of the three interaction sites contributes to an avid interface between CRBN and KAT2A and is indispensable for KAT2A recognition”
The paper relies on this without support.
The cryo-EM ternary complex structure represents the relevant solution-state recruitment interface.
“To visualize how 4 induces the recruitment of KAT2A to CRBN, we determined a 2.9 Å resolution cryo-EM structure of the DDB1ΔB-CRBN-4-KAT2ANTD ternary complex”
“The structure showed clear density for each protein and unambiguous density for 4 at the interface between CRBN and KAT2ANTD”
The paper relies on this without support.
The internal degradation proteomics database is comprehensive enough to identify KAT2A-targeting molecular glues.
“Initial KAT2A-targeting MG degrader hits were obtained by interrogating our database of target-agnostic global degradation proteomics (34, 35) and immunoprecipitation mass spectrometry (IP-MS) (12)”
Cites
Highly accurate protein structure prediction with AlphaFold
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Targeted protein degradation: from mechanisms to clinic
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Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development
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MYC—Master Regulator of the Cancer Epigenome and Transcriptome
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Mining the CRBN target space redefines rules for molecular glue-induced neosubstrate recognition
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Selective Degradation of GSPT1 by Cereblon Modulators Identified via a Focused Combinatorial Library
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Self-citationHistone lysine acetyltransferase inhibitors: an emerging class of drugs for cancer therapy
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N-Myc and GCN5 Regulate Significantly Overlapping Transcriptional Programs in Neural Stem Cells
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Unveiling the hidden interactome of CRBN molecular glues
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Self-citationLoss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
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Induced proximity-based therapeutic modalities
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Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives
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Transcriptional Activation of MYC-Induced Genes by GCN5 Promotes B-cell Lymphomagenesis
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High-throughput ligand diversification to discover chemical inducers of proximity
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Self-citationLysine Acetyltransferases and Their Role in AR Signaling and Prostate Cancer
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Cereblon induces G3BP2 neosubstrate degradation using molecular surface mimicry
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Research works printed but not linked: 1
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Cited by
Sorted by citations
Disrupting a Convergent Acetylation Circuit Collapses Leukemic Identity Across AML SubtypesPreprint
Deshpande, A., Chiang, C.-Y., Perales, M., Niranjan, N., Sinha, N., Finlay, D., Stevens, A., Zahn, E., Garcia, B. A., Jeremias, I., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.07.13.737885
Expanding the molecular glue target space
Villanueva, M. T. (2026) · Nature Reviews Drug Discovery · doi:10.1038/d41573-026-00132-3
Anew Labs Team, & Liu, K. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.20.752967
- Authors
- Ojeda, S., Wang, M., Baek, K., Bourgeois, W., Sommerschield, A., Yue, H., Metivier, R. J., Karagiannis, P., Levitz, T. S., Xiong, Y., Donovan, K. A., Armstrong, S. A., & Fischer, E. S.
- Affiliations
- Harvard University (US)
- Boston Children's Hospital (US)
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Corresponding author
- Ojeda, Samuel
- Wang, Meng
- Fischer, Eric S.
- ORCID
- Venue
- Science
- Published
- 2026-07-09
- Volume
- 393
- Issue
- 6807
- Pages
- 188-194
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC13423211
- OpenAlex
- W7167835863
- Cited by
- 5
- References
- 56
- Citations by year
- 2026: 5
- FWCI
- 10.22
- Type
- journal article
- Language
- en
- Open access
- green
- pmc.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01CA262188, R01CA214608, R01CA218278, P01CA066996)
- Damon Runyon Cancer Research Foundation (DRG-2514-24)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- GCN5, cereblon, histone acetyltransferase, H3K9 acetylation, acute myeloid leukemia, patient-derived xenografts
- MeSH terms
- Proteolysis Targeting Chimera, Degrons, Acetylation, Animals, Histones, Humans, Histone-Lysine N-Methyltransferase, Tyrosine, Leukemia, Myeloid, Acute, Cryoelectron Microscopy, Xenograft Model Antitumor Assays, Ubiquitin-Protein Ligases, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Histone Acetyltransferases, Myeloid-Lymphoid Leukemia Protein, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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