Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation

Cromm, Philipp M.; Samarasinghe, Kusal T. G.; Hines, John; Crews, Craig M.

doi:10.1021/jacs.8b08008

Cited by 311Protein Degradation and InhibitorsChemical Synthesis and AnalysisUbiquitin and proteasome pathways

Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation

Cromm, Philipp M., Samarasinghe, Kusal T. G., Hines, John, Crews, Craig M.·2018·Journal of the American Chemical Society

DOI 10.1021/jacs.8b08008

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Abstract

Enzymatic inhibition has proven to be a successful modality for the development of many small-molecule drugs. In recent years, small-molecule-induced protein degradation has emerged as an orthogonal therapeutic strategy that has the potential to expand the druggable target space. Focal adhesion kinase (Fak) is a key player in tumor invasion and metastasis, acting simultaneously as a kinase and a scaffold for several signaling proteins. While previous efforts to modulate Fak activity were limited to kinase inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously block Fak's kinase signaling and scaffolding capabilities. Here, we report the development of a selective and potent Fak degrader, PROTAC-3, which outperforms a clinical candidate, defactinib, with respect to Fak activation as well as Fak-mediated cell migration and invasion. These results underline the potential that PROTACs offer in expanding the druggable space and controlling protein functions that are not easily addressed by traditional small-molecule therapeutics.

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Beginning a targeted protein degrader discovery project with solid prior knowledge of optimal chemotype-target pairs can rapidly speed up hit-to-lead time.
“Beginning a targeted protein degrader discovery project with solid prior knowledge of optimal chemotype-target pairs can rapidly speed up hit-to-lead time (Brand et al., 2019; Cromm et al., 2018; Dobrovolsky et al., 2019; Jiang et al., 2019; Li et al., 2019; Olson et al., 2018).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Cromm et al., 2018
Degraders result in loss of both enzymatic and non-enzymatic functions of proteins, such as the scaffolding function of kinases or the gene regulatory functions of transcriptional effectors.
“Degraders result in loss of both enzymatic and non-enzymatic functions of proteins, such as the scaffolding function of kinases (Cromm et al., 2018), or the gene regulatory functions of transcriptional effectors (Winter et al., 2015).”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Cromm et al., 2018
Targeted protein degraders, also known as PROTACs, are an emerging strategy for ablating previously undruggable protein functions.
“Targeted protein degraders, also known as PROTACs (PROteolysis TArgeting Chimeras), are an emerging strategy for ablating previously undruggable protein functions”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as Cromm et al., 2018
A FAK degrader was proven to be beneficial by inhibiting its non-enzymatic function.
“a FAK degrader was proven to be beneficial by inhibiting its non-enzymatic function [49].”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [49]
AR, ER, FAK, P38 PROTACs have been developed against different solid tumors.
“For example, PROTACs against BRD4, BTK, BCR-ABL and CDK-6 etc. have shown efficacy in leukemia [22, 44, 58, 60], whereas AR, ER, FAK, P38 PROTACs have been developed against different solid tumors [13, 49, 51, 104] (Table 1).”
From PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics (2020) · cites this paper as [49]

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PROteolysis TArgeting Chimeras (PROTACs) as emerging anticancer therapeutics
Khan, S., He, Y., Zhang, X., Yuan, Y., Pu, S., Kong, Q., Zheng, G., & Zhou, D. (2020) · Oncogene · doi:10.1038/s41388-020-1336-y · Cited by 252 · see citing works
Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands
Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., Xu, T., Wang, M., Yang, C., Chinnaswamy, K., Stuckey, J. A., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01393 · Cited by 229 · see citing works
Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation
Burslem, G. M., Schultz, A. R., Bondeson, D. P., Eide, C. A., Savage Stevens, S. L., Druker, B. J., & Crews, C. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-1236 · Cited by 212 · see citing works
“The ability of PROTACs to induce degradation of the target is not limited to binding sites within the kinase domain, but have the potential to be implemented when kinase activity is not the singular role of the target protein (13).”
Recent Developments in PROTAC‐Mediated Protein Degradation: From Bench to Clinic
Hu, Z., & Crews, C. M. (2022) · ChemBioChem · doi:10.1002/cbic.202100270 · Cited by 231 · see citing works
Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches
Saraon, P., Pathmanathan, S., Snider, J. D., Lyakisheva, A., Wong, V., & Štagljar, I. (2021) · Oncogene · doi:10.1038/s41388-021-01841-2 · Cited by 212 · see citing works
Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders
Su, S., Yang, Z., Gao, H., Yang, H., Zhu, S., An, Z., Wang, J., Li, Q., Chandarlapaty, S., Deng, H., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b00871 · Cited by 209 · see citing works
Prey for the Proteasome: Targeted Protein Degradation—A Medicinal Chemist's Perspective
Luh, L. M., Scheib, U., Juenemann, K., Wortmann, L., Brands, M., & Cromm, P. M. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202004310 · Cited by 200 · see citing works
From Conception to Development: Investigating PROTACs Features for Improved Cell Permeability and Successful Protein Degradation
Cecchini, C., Pannilunghi, S., Tardy, S., & Scapozza, L. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.672267 · Cited by 198 · see citing works
Discovery of Potent and Selective Epidermal Growth Factor Receptor (EGFR) Bifunctional Small-Molecule Degraders
Cheng, M., Yu, X., Lu, K. J., Xie, L., Wang, L., Meng, F., Han, X., Chen, X., Liu, J., Xiong, Y., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01566 · Cited by 197 · see citing works
Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood–Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2
Liu, X., Kalogeropulou, A. F., Domingos, S., Makukhin, N., Nirujogi, R. S., Singh, F., Shpiro, N., Saalfrank, A., Sammler, E. M., Ganley, I. G., et al. (2022) · Journal of the American Chemical Society · doi:10.1021/jacs.2c05499 · Cited by 198 · see citing works
PROTACs: A novel strategy for cancer therapy
Liu, J., Ma, J., Liu, Y., Xia, J., Li, Y., Wang, Z. P., & Wei, W. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.02.006 · Cited by 186 · see citing works
PROTACs to address the challenges facing small molecule inhibitors
Martín-Acosta, P., & Xiao, X. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112993 · Cited by 186 · see citing works
Harnessing the Power of Proteolysis for Targeted Protein Inactivation
Verma, R., Mohl, D., & Deshaies, R. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.010 · Cited by 185 · see citing works
PROTACs– a game-changing technology
Konstantinidou, M., Li, J., Zhang, B., Wang, Z., Shaabani, S., ter Brake, F., Essa, K., & Dömling, A. S. S. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1659242 · Cited by 167 · see citing works
“On the contrary, in some cases, such as the targeting of focal adhesion kinase (Fak) [84], where kinase inhibitors have a low success rate in clinical trials, the optimized clinical candidate defactinib was outperformed by the designed PROTAC.”
Method
The role of reversible and irreversible covalent chemistry in targeted protein degradation
Kiely‐Collins, H., Winter, G. E., & Bernardes, G. J. L. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.03.005 · Cited by 156 · see citing works
“targets including kinases (Bondeson et al., 2015; Buhimschi et al., 2018; Cromm et al., 2018; Olson et al., 2018; Powell et al., 2018; Sun et al., 2018), bromodomains (Bai et al.”
Background
DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs
Li, F., Hu, Q., Zhang, X., Sun, R., Liu, Z., Wu, S., Tian, S., Ma, X., Dai, Z., Yang, X., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34807-3 · Cited by 159 · see citing works
Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta
Bai, N., Miller, S. A., Andrianov, G. V., Yates, M., Kirubakaran, P., & Karanicolas, J. (2021) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c01451 · Cited by 157 · see citing works
Focal adhesion kinase: from biological functions to therapeutic strategies
Tan, X., Yan, Y., Song, B., Zhu, S., Mei, Q., & Wu, K. (2023) · Experimental Hematology & Oncology · doi:10.1186/s40164-023-00446-7 · Cited by 158 · see citing works
“Recently, an effective FAK degradation agents have been developed that can selectively degrade FAK and showed outstanding inhibitory effects in triple-negative breast cancer and ovarian cancer cells [173, 174].”
Background
Expanding the arsenal of E3 ubiquitin ligases for proximity-induced protein degradation
Kannt, A., & Đikić, I. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.04.007 · Cited by 148 · see citing works
The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination
Jin, J., Wu, Y., Chen, J., Shen, Y., Zhang, L., Zhang, H., Chen, L., Yuan, H., Chen, H., Zhang, W., et al. (2020) · Theranostics · doi:10.7150/thno.46985 · Cited by 146 · see citing works
“As a vital direction for novel drug discovery, the therapeutic strategies of PROTAC have been successfully applied to conditionally degrade plenty of POIs in vitro and in vivo, such as estrogen receptor (ER) [7], androgen receptor (AR) [8], bromodomain-containing protein 4 (BRD4) [9-11], anaplastic lymphoma kinase (AL…”
Background
Characteristic roadmap of linker governs the rational design of PROTACs
Dong, Y., Ma, T., Xu, T., Feng, Z., Li, Y., Song, L., Yao, X., Ashby, C. R., & Hao, G.-F. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.04.007 · Cited by 146 · see citing works
Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity
Klein, V. G., Bond, A. G., Craigon, C., Lokey, R. S., & Ciulli, A. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01496 · Cited by 152 · see citing works
“74 − 33 In this study, we have shown that PAMPA is a reliable predictor of PROTAC permeability that translates relatively well Journal of Medicinal Chemistry into their cellular activity pro ﬁ les.”
Strategies toward Discovery of Potent and Orally Bioavailable Proteolysis Targeting Chimera Degraders of Androgen Receptor for the Treatment of Prostate Cancer
Han, X., Zhao, L., Xiang, W., Qin, C., Miao, B., McEachern, D., Wang, Y., Metwally, H., Wang, L., Matvekas, A., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00882 · Cited by 170 · see citing works
A potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Bery, N., Miller, A., & Rabbitts, T. (2020) · Nature Communications · doi:10.1038/s41467-020-17022-w · Cited by 132 · see citing works
Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory
Cowan, A. D., & Ciulli, A. (2022) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-032620-104421 · Cited by 129 · see citing works
Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling
You, I., Erickson, E. C., Donovan, K. A., Eleuteri, N. A., Fischer, E. S., Gray, N. S., & Toker, A. (2019) · Cell chemical biology · doi:10.1016/j.chembiol.2019.11.014 · Cited by 132 · see citing works
The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells
Kurimchak, A. M., Herrera-Montávez, C., Montserrat-Sangrà, S., Araiza-Olivera, D., Hu, J., Neumann-Domer, R., Kuruvilla, M., Bellacosa, A., Testa, J. R., Jin, J., et al. (2022) · Science Signaling · doi:10.1126/scisignal.abn2707 · Cited by 136 · see citing works
“In addition, cotreatment of DLD-1 cells with focal adhesion kinase (FAK) degrader (FAK-degrader-1) (32) or mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) degrader (MS432) (33) and tariquidar enhanced the protein reduction relative to single-agent therapies (fig.”
Background
Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs
Law, R. P., Nunes, J., Chung, C., Bantscheff, M., Buda, K., Dai, H., Evans, J. P., Flinders, A., Klimaszewska, D., Lewis, A. J., et al. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202109237 · Cited by 121 · see citing works
Strategies for designing proteolysis targeting chimaeras (PROTACs)
He, S., Dong, G., Cheng, J., Wu, Y., & Sheng, C. (2022) · Medicinal Research Reviews · doi:10.1002/med.21877 · Cited by 118 · see citing works
“At concentrations ranging from 10 to 40 nM, an initially developed FAK‐targeting PROTAC degraded only one‐half of the FAK proteins to which it was exposed.(83) After introducing the triazole group, the half‐maximal degradation rate (DC50) of compound 43 was improved: 30 pM.”
BackgroundMethod
A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Tong, B., Spradlin, J. N., Novaes, L. F. T., Zhang, E., Hu, X., Moeller, M., Brittain, S. M., McGregor, L. M., McKenna, J. M., Tallarico, J. A., et al. (2020) · ACS Chemical Biology · doi:10.1021/acschembio.0c00348 · Cited by 118 · see citing works
PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy
Kelm, J. M., Pandey, D. S., Malin, E., Kansou, H. W., Arora, S., Kumar, R., & Gavande, N. S. (2023) · Molecular Cancer · doi:10.1186/s12943-022-01707-5 · Cited by 115 · see citing works
PROTACs: Emerging Targeted Protein Degradation Approaches for Advanced Druggable Strategies
Sincere, N. I., Anand, K., Ashique, S., Yang, J., & You, C. (2023) · Molecules · doi:10.3390/molecules28104014 · Cited by 109 · see citing works
Progress in the Development of Small Molecular Inhibitors of Focal Adhesion Kinase (FAK)
Lu, Y., & Sun, H. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01248 · Cited by 106 · see citing works
Plasticity in designing PROTACs for selective and potent degradation of HDAC6
Yang, H., Lv, W., He, M., Deng, H., Li, H., Wu, W., & Rao, Y. (2019) · Chemical Communications · doi:10.1039/c9cc08509b · Cited by 108 · see citing works
Target protein localization and its impact on PROTAC-mediated degradation
Simpson, L. M., Glennie, L., Brewer, A., Zhao, J., Crooks, J., Shpiro, N., & Sapkota, G. P. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.08.004 · Cited by 100 · see citing works
Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader
Tovell, H., Testa, A., Zhou, H., Shpiro, N., Crafter, C., Ciulli, A., & Alessi, D. R. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00505 · Cited by 95 · see citing works
Protein degradation technology: a strategic paradigm shift in drug discovery
Li, H., Dong, J., Cai, M., Xu, Z., Cheng, X., & Qin, J. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-021-01146-7 · Cited by 93 · see citing works
Chemo-proteomics exploration of HDAC degradability by small molecule degraders
Xiong, Y., Donovan, K. A., Eleuteri, N. A., Kirmani, N., Yue, H., Razov, A., Krupnick, N. M., Nowak, R. P., & Fischer, E. S. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.07.002 · Cited by 90 · see citing works
Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor
Niu, T., Li, K., Li, J., Zhou, Z., Hong, J.-E., Chen, X., Dong, X., He, Q., Cao, J., Yang, B., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.114012 · Cited by 90 · see citing works
Roles and inhibitors of FAK in cancer: current advances and future directions
Hu, H.-H., Wang, S., Shang, H.-L., Lv, H., Chen, B., Gao, S., & Chen, X. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1274209 · Cited by 89 · see citing works
Extracellular matrix-mediated regulation of cancer stem cells and chemoresistance
Brown, Y., Hua, S., & Tanwar, P. S. (2019) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2019.02.002 · Cited by 88 · see citing works
Blocking Non-enzymatic Functions by PROTAC-Mediated Targeted Protein Degradation
Sun, D., Zhang, J., Dong, G., He, S., & Sheng, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01159 · Cited by 88 · see citing works
Design, Synthesis, and Evaluation of Highly Potent FAK-Targeting PROTACs
Gao, H., Wu, Y., Sun, Y., Yang, Y., Zhou, G., & Rao, Y. (2019) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00372 · Cited by 87 · see citing works
Proteolysis targeting chimeras (PROTACs) in cancer therapy
Ocaña, A., & Pandiella, A. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01672-1 · Cited by 87 · see citing works
PROTAC therapy as a new targeted therapy for lung cancer
Li, J. W., Zheng, G., Kaye, F. J., & Wu, L. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2022.11.011 · Cited by 87 · see citing works
“56 – 58 Up-regulation of total or phosphorylated STAT3 was associated with poor prognosis in patients with NSCLCs and thus STAT3 is an attractive therapeutic target.”
Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies
Silva, M. C., & Haggarty, S. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21238948 · Cited by 87 · see citing works
PROTAC: A promising technology for cancer treatment
Zhou, X., Dong, R., Zhang, J., Zheng, X. X., & Sun, L. (2020) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2020.112539 · Cited by 84 · see citing works
Utilizing PROTAC technology to address the on-target platelet toxicity associated with inhibition of BCL-X <sub>L</sub>
Zhang, X., Thummuri, D., He, Y., Liu, X., Zhang, P., Zhou, D., & Zheng, G. (2019) · Chemical Communications · doi:10.1039/c9cc07217a · Cited by 86 · see citing works
Targeting the Ubiquitin-Proteasome System for Cancer Therapeutics by Small-Molecule Inhibitors
LaPlante, G., & Zhang, W. (2021) · Cancers · doi:10.3390/cancers13123079 · Cited by 82 · see citing works
FAK suppresses antigen processing and presentation to promote immune evasion in pancreatic cancer
Canel, M., Sławińska, A., Lonergan, D. W., Kallor, A. A., Upstill‐Goddard, R., Davidson, C., von Kriegsheim, A., Biankin, A. V., Byron, A., Alfaro, J. A., et al. (2023) · Gut · doi:10.1136/gutjnl-2022-327927 · Cited by 81 · see citing works
Constructions of ROS-responsive titanium-hydroxyapatite implant for mesenchymal stem cell recruitment in peri-implant space and bone formation in osteoporosis microenvironment
Chen, M., Sun, Y., Hou, Y., Luo, Z. Y., Li, M., Wei, Y., Chen, M., Tan, L., Cai, K., & Hu, Y. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.02.006 · Cited by 79 · see citing works
Recent Advances in PROTACs for Drug Targeted Protein Research
Yao, T., Xiao, H., Wang, H., & Xu, X. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810328 · Cited by 78 · see citing works
“The Crews group synthesized PROTAC 3, a Fak degrader (Table 1), which significantly exceeded the FAK inhibitor defactinib [37] in Fak signaling and cell migration and invasion in human triple-negative breast cancer (TNBC) cells.”
Background
Assays and Technologies for Developing Proteolysis Targeting Chimera Degraders
Liu, X., Zhang, X., Lv, D., Yuan, Y., Zheng, G., & Zhou, D. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0073 · Cited by 73 · see citing works
“For example, basic nitrogen-containing groups such as a pyridinyl or a piperazinyl group were empirically introduced in the linker to increase the solubility of PROTACs [23], while an amide bond was avoided in an attempt to improve permeability [24].”
Background
Targeted protein degradation in vivo with Proteolysis Targeting Chimeras: Current status and future considerations
Watt, G. F., Scott‐Stevens, P., & Gaohua, L. (2019) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2019.02.005 · Cited by 72 · see citing works
“by the differentiated biological profile demonstrated with P300/CBP-associated factor/general control nonderepressible 5 (PCAF/GCN5) PROTACs [16] and Focal Adhesion Kinase (FAK) PROTACs [17].”
Background
A NSD3-targeted PROTAC suppresses NSD3 and cMyc oncogenic nodes in cancer cells
Xu, C., Meng, F., Park, K., Storey, A. J., Gong, W., Tsai, Y., Gibson, E., Byrum, S. D., Li, D., Edmondson, R. D., et al. (2021) · Cell chemical biology · doi:10.1016/j.chembiol.2021.08.004 · Cited by 72 · see citing works
Evolution of Cereblon-Mediated Protein Degradation as a Therapeutic Modality
Chamberlain, P. P., D’Agostino, L. A., Ellis, J. M., Hansen, J. D., Matyskiela, M. E., McDonald, J. J., Riggs, J. R., & Hamann, L. G. (2019) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00425 · Cited by 69 · see citing works
VHL-based PROTACs as potential therapeutic agents: Recent progress and perspectives
Wang, C., Zhang, Y., Wang, J., & Xing, D. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113906 · Cited by 71 · see citing works
Discovery of Novel PDEδ Degraders for the Treatment of KRAS Mutant Colorectal Cancer
Cheng, J., Li, Y., Wang, X., Dong, G., & Sheng, C. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00929 · Cited by 67 · see citing works
Transforming targeted cancer therapy with PROTACs: A forward-looking perspective
Farnaby, W., Koegl, M., McConnell, D. B., & Ciulli, A. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.02.009 · Cited by 66 · see citing works
Targeted protein degradation in cancers: Orthodox PROTACs and beyond
Li, J., Chen, X., Lü, A., & Liang, C. (2023) · The Innovation · doi:10.1016/j.xinn.2023.100413 · Cited by 66 · see citing works
Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery
Pei, H., Peng, Y., Zhao, Q., & Chen, Y. (2019) · RSC Advances · doi:10.1039/c9ra03423d · Cited by 65 · see citing works
Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation
Zhang, J., Fu, L., Shen, B., Liu, Y., Wang, W., Cai, X., Kong, L., Yan, Y., Meng, R., Zhang, Z., et al. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.08.010 · Cited by 63 · see citing works
Journey of PROTAC: From Bench to Clinical Trial and Beyond
Berkley, K., Zalejski, J., Sharma, N., & Sharma, A. K. (2025) · Biochemistry · doi:10.1021/acs.biochem.4c00577 · Cited by 62 · see citing works
Opportunities and Challenges of Small Molecule Induced Targeted Protein Degradation
He, M., Lv, W., & Rao, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.685106 · Cited by 62 · see citing works
The Development of FAK Inhibitors: A Five-Year Update
Spallarossa, A., Tasso, B., Russo, E., Villa, C., & Brullo, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126381 · Cited by 58 · see citing works
“Name Chemical Structure Phase Number of Clinical Trial IC50 on FAK Defactinib Int.”
ResultInfluential
Current advances of small molecule E3 ligands for proteolysis-targeting chimeras design
Mi, D., Li, Y., Gu, H., Li, Y., & Chen, Y. (2023) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2023.115444 · Cited by 57 · see citing works
Small molecule PROTACs in targeted therapy: An emerging strategy to induce protein degradation
Xi, M., Chen, Y., Yang, H., Xu, H., Du, K., Wu, C., Xu, Y., Deng, L., Luo, X., Yu, L., et al. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.04.036 · Cited by 56 · see citing works
Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders
Chen, L., Chen, Y., Zhang, C., Jiao, B., Liang, S., Qiong, T., Chai, H., Yu, W., Qian, Y., Yang, H., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01342 · Cited by 55 · see citing works
Targeting Protein Kinases Degradation by PROTACs
Yu, F., Cai, M., Shao, L., & Zhang, J. (2021) · Frontiers in Chemistry · doi:10.3389/fchem.2021.679120 · Cited by 54 · see citing works
“Moreover, PROTAC-3 was reported to improve selectivity over defactinib, as it only binds to FAK with less than 1% of the control compound remaining (Cromm et al., 2018).”
Background
Targeting focal adhesion kinase (FAK) for cancer therapy: FAK inhibitors, FAK-based dual-target inhibitors and PROTAC degraders
Yang, M. J., Xiang, H., & Luo, G. (2024) · Biochemical Pharmacology · doi:10.1016/j.bcp.2024.116246 · Cited by 53 · see citing works
Targeting the Non-Catalytic Functions: a New Paradigm for Kinase Drug Discovery?
Wang, Z., Huang, W., Zhou, K., Ren, X., & Ding, K. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01978 · Cited by 52 · see citing works
Discovery and Optimization of Tau Targeted Protein Degraders Enabled by Patient Induced Pluripotent Stem Cells-Derived Neuronal Models of Tauopathy
Silva, M. C., Nandi, G., Donovan, K. A., Cai, Q., Berry, B. C., Nowak, R. P., Fischer, E. S., Gray, N. S., Ferguson, F. M., & Haggarty, S. J. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.801179 · Cited by 50 · see citing works
“, cereblon or CRBN) recruiting molecule such as an immunomodulatory drug (IMiD) (Figures 1A–C; Xie et al., 2014; Lai and Crews, 2017; Cromm et al., 2018; Gechijian et al., 2018).”
Background
Proteasome-Independent Protein Knockdown by Small-Molecule Inhibitor for the Undruggable Lung Adenocarcinoma
Zhou, W., Sun, G., Zhang, Z., Zhao, L., Xu, L., Yuan, H., Li, S., Dong, Z., Song, Y., & Fang, X. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b08777 · Cited by 49 · see citing works

Development and Characterization of Selective FAK Inhibitors and PROTACs with In Vivo Activity
Koide, E., Mohardt, M. L., Doctor, Z. M., Yang, A., Hao, M., Donovan, K. A., Kuismi, C. C., Nelson, A. J., Abell, K., Aguiar, M., et al. (2023) · ChemBioChem · doi:10.1002/cbic.202300141 · Cited by 17 · see citing works
Identification of novel and potent PROTACs targeting FAK for non-small cell lung cancer: Design, synthesis, and biological study
Sun, Y., Wang, R., Sun, Y., Wang, L., Xue, Y., Wang, J., Wu, T., Yin, W., Qin, Q., Sun, Y., et al. (2022) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2022.114373 · Cited by 33 · see citing works
Design, synthesis, and biological evaluation of potent FAK-degrading PROTACs
Qin, Q., Wang, R., Fu, Q., Zhang, G., Wu, T., Liu, N., Lv, R., Yin, W., Sun, Y., Sun, Y., et al. (2022) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2022.2100886 · Cited by 24 · see citing works
Modeling of FAK-PROTAC candidates from GSK2256098 analogs for targeted protein degradation
Kumar, V., Parate, S., Ro, H., Jung, T. S., & Lee, K. W. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.151001 · Cited by 1 · see citing works
Discovery and Characterisation of Highly Cooperative FAK‐Degrading PROTACs
Law, R. P., Nunes, J., Chung, C., Bantscheff, M., Buda, K., Dai, H., Evans, J. P., Flinders, A., Klimaszewska, D., Lewis, A. J., et al. (2021) · Angewandte Chemie · doi:10.1002/ange.202109237 · Cited by 5 · see citing works

Authors: Cromm, P. M., Samarasinghe, K. T. G., Hines, J., & Crews, C. M.
Affiliations: Yale University (US)
Corresponding author: Crews, Craig M.
ORCID: Cromm, Philipp M.
Samarasinghe, Kusal T. G.
Crews, Craig M.
Venue: Journal of the American Chemical Society
Publisher: American Chemical Society (ACS)
Published: 2018-11-16
Volume: 140
Issue: 49
Pages: 17019-17026
ISSN: 0002-7863 (ISSN-L)
1520-5126
DOI: 10.1021/jacs.8b08008
OpenAlex: W2901669535
Cited by: 293
References: 47
Citations by year: 2026: 30 · 2025: 29 · 2024: 41 · 2023: 25 · 2022: 43 · 2021: 49 · 2020: 46 · 2019: 29 · 2018: 1
FWCI: 11.38
Type: journal article
Language: en
Open access: closed
Locations: Journal of the American Chemical Society (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R35CA197589, R50CA211252)
Alexander von Humboldt-Stiftung
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: focal adhesion kinase, PROTACs, defactinib, tumor invasion, metastasis, cell migration, PROTAC design
MeSH terms: Antineoplastic Agents, Benzamides, Cell Movement, Humans, Pyrazines, Sulfonamides, Drug Design, Signal Transduction, Cell Line, Tumor, Protein Kinase Inhibitors, Focal Adhesion Kinase 1, Proteolysis

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Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation

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