Proteolysis targeting chimeras (PROTACs) in ‘beyond rule-of-five’ chemical space: Recent progress and future challenges

Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1

Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139 · see citing works

Molecular properties that influence the oral bioavailability of drug candidates

Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm020017n · Cited by 8,420 · see citing works

The druggable genome

Hopkins, A. L., & Groom, C. R. (2002) · Nature Reviews Drug Discovery · doi:10.1038/nrd892 · Cited by 3,305 · see citing works

Peptide therapeutics: current status and future directions

Fosgerau, K., & Hoffmann, T. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.10.003 · Cited by 3,060 · see citing works

The influence of drug-like concepts on decision-making in medicinal chemistry

Leeson, P. D., & Springthorpe, B. (2007) · Nature Reviews Drug Discovery · doi:10.1038/nrd2445 · Cited by 2,403 · see citing works

Phthalimide conjugation as a strategy for in vivo target protein degradation

Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760 · see citing works

Prediction of Physicochemical Parameters by Atomic Contributions

Wildman, S. A., & Crippen, G. M. (1999) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci990307l · Cited by 1,491 · see citing works

Induced protein degradation: an emerging drug discovery paradigm

Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486 · see citing works

Catalytic in vivo protein knockdown by small-molecule PROTACs

Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356 · see citing works

The therapeutic monoclonal antibody market

Ecker, D. M., Jones, S. D., & Levine, H. L. (2014) · mAbs · doi:10.4161/19420862.2015.989042 · Cited by 1,292 · see citing works

Structural basis of PROTAC cooperative recognition for selective protein degradation

Gadd, M. S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D. J., Zengerle, M., & Ciulli, A. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2329 · Cited by 1,242 · see citing works

Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4

Lu, J., Qian, Y., Altieri, M., Dong, H., Wang, J., Raina, K., Hines, J., Winkler, J. D., Crew, A. P., Coleman, K., et al. (2015) · Chemistry & Biology · doi:10.1016/j.chembiol.2015.05.009 · Cited by 1,140 · see citing works

The dTAG system for immediate and target-specific protein degradation

Nabet, B., Roberts, J. M., Buckley, D. L., Paulk, J., Dastjerdi, S., Yang, A., Leggett, A. L., Erb, M. A., Lawlor, M. A., Souza, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0021-8 · Cited by 1,118 · see citing works

Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4

Zengerle, M., Chan, K.-H., & Ciulli, A. (2015) · ACS Chemical Biology · doi:10.1021/acschembio.5b00216 · Cited by 1,056 · see citing works

PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521738113 · Cited by 852 · see citing works

Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides

Geary, R. S., Norris, D. A., Yu, R. Z., & Bennett, C. F. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.01.008 · Cited by 846 · see citing works

Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates

Doak, B. C., Over, B., Giordanetto, F., & Kihlberg, J. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.013 · Cited by 835 · see citing works

Knocking down disease: a progress report on siRNA therapeutics

Wittrup, A., & Lieberman, J. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3978 · Cited by 810 · see citing works

The Advantages of Targeted Protein Degradation Over Inhibition: An RTK Case Study

Burslem, G. M., Smith, B. E., Lai, A. C., Jaime-Figueroa, S., McQuaid, D. C., Bondeson, D. P., Toure, M., Dong, H., Qian, Y., Wang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.009 · Cited by 686 · see citing works

Advances in the delivery of RNA therapeutics: from concept to clinical reality

Kaczmarek, J. C., Kowalski, P. S., & Anderson, D. G. (2017) · Genome Medicine · doi:10.1186/s13073-017-0450-0 · Cited by 656 · see citing works

Targeted intracellular protein degradation induced by a small molecule: En route to chemical proteomics

Schneekloth, A. R., Pucheault, M., Tae, H. S., & Crews, C. M. (2008) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2008.07.114 · Cited by 635 · see citing works

Modular PROTAC design for the degradation of oncogenic BCR-ABL

Lai, A. C., Toure, M., Hellerschmied, D., Salami, J., Jaime‐Figueroa, S., Ko, E., Hines, J., & Crews, C. M. (2016) · Angewandte Chemie International Edition · doi:10.1002/anie.201507634 · Cited by 618 · see citing works

Targeting the von Hippel-Lindau E3 ubiquitin ligase using small molecules to disrupt the VHL/HIF-1α interaction

Buckley, D. L., Van Molle, I., Gareiss, P. C., Tae, H. S., Michel, J., Noblin, D. J., Jorgensen, W. L., Ciulli, A., & Crews, C. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja209924v · Cited by 569 · see citing works

Pharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation

Olson, C. M., Jiang, B., Erb, M. A., Liang, Y., Doctor, Z. M., Zhang, Z., Zhang, T., Kwiatkowski, N., Boukhali, M., Green, J. L., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2538 · Cited by 552 · see citing works

Three decades of nucleic acid aptamer technologies: Lessons learned, progress and opportunities on aptamer development

Wang, T., Chen, C., Larcher, L. M., Barrero, R. A., & Veedu, R. N. (2018) · Biotechnology Advances · doi:10.1016/j.biotechadv.2018.11.001 · Cited by 531 · see citing works

Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?

Churcher, I. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01272 · Cited by 491 · see citing works

A Chemoproteomic Approach to Query the Degradable Kinome Using a Multi-kinase Degrader

Huang, H.-T., Dobrovolsky, D., Paulk, J., Yang, G., Weisberg, E. L., Doctor, Z. M., Buckley, D. L., Cho, J.-H., Ko, E., Jang, J., et al. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.10.005 · Cited by 437 · see citing works

Delineating the role of cooperativity in the design of potent PROTACs for BTK

Zorba, A., Nguyen, C., Xu, Y., Starr, J., Borzilleri, K., Smith, J., Zhu, H., Farley, K. A., Ding, W., Schiemer, J., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1803662115 · Cited by 419 · see citing works

Protein Knockdown Using Methyl Bestatin−Ligand Hybrid Molecules: Design and Synthesis of Inducers of Ubiquitination-Mediated Degradation of Cellular Retinoic Acid-Binding Proteins

Itoh, Y., Ishikawa, M., Naito, M., & Hashimoto, Y. (2010) · Journal of the American Chemical Society · doi:10.1021/ja100691p · Cited by 404 · see citing works

Discovery of ARD-69 as a Highly Potent Proteolysis Targeting Chimera (PROTAC) Degrader of Androgen Receptor (AR) for the Treatment of Prostate Cancer

Han, X., Wang, C., Qin, C., Xiang, W., Fernández‐Salas, E., Yang, C., Wang, M., Zhao, L., Xu, T., Chinnaswamy, K., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01631 · Cited by 404 · see citing works

Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation

Buhimschi, A. D., Armstrong, H. A., Toure, M., Jaime-Figueroa, S., Chen, T. L., Lehman, A. M., Woyach, J. A., Johnson, A. J., Byrd, J. C., & Crews, C. M. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00391 · Cited by 394 · see citing works

Beyond the Rule of 5: Lessons Learned from AbbVie’s Drugs and Compound Collection

DeGoey, D. A., Chen, H.-J., Cox, P. B., & Wendt, M. D. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00717 · Cited by 387 · see citing works

Two Decades under the Influence of the Rule of Five and the Changing Properties of Approved Oral Drugs.

Shultz, M. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00686 · Cited by 375 · see citing works

Discovery of a Small-Molecule Degrader of Bromodomain and Extra-Terminal (BET) Proteins with Picomolar Cellular Potencies and Capable of Achieving Tumor Regression

Zhou, B. N., Hu, J., Xu, F., Chen, Z., Bai, L., Fernández‐Salas, E., Lin, M., Liu, L., Yang, C., Zhao, Y., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01816 · Cited by 373 · see citing works

Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs

An, S., & Fu, L. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.005 · Cited by 363 · see citing works

MDM2-Recruiting PROTAC Offers Superior, Synergistic Antiproliferative Activity via Simultaneous Degradation of BRD4 and Stabilization of p53

Hines, J., Lartigue, S., Dong, H., Qian, Y., & Crews, C. M. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2918 · Cited by 348 · see citing works

How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets

Doak, B. C., Zheng, J., Dobritzsch, D., & Kihlberg, J. O. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01286 · Cited by 344 · see citing works

Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel–Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7

Zoppi, V., Hughes, S. J., Maniaci, C., Testa, A., Gmaschitz, T., Wieshofer, C., Koegl, M., Riching, K. M., Daniels, D. L., Spallarossa, A., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b01413 · Cited by 336 · see citing works

The PROTAC technology in drug development

Zou, Y., Ma, D., & Wang, Y. (2019) · Cell Biochemistry and Function · doi:10.1002/cbf.3369 · Cited by 307 · see citing works

PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies

Sun, Y., Zhao, X., Ding, N., Gao, H., Wu, Y., Yang, Y., Zhao, M., Hwang, J., Song, Y., Liu, W., et al. (2018) · Cell Research · doi:10.1038/s41422-018-0055-1 · Cited by 295 · see citing works

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

Cromm, P. M., Samarasinghe, K. T. G., Hines, J., & Crews, C. M. (2018) · Journal of the American Chemical Society · doi:10.1021/jacs.8b08008 · Cited by 293 · see citing works

Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

Qin, C., Hu, Y., Zhou, B., Fernandez-Salas, E., Yang, C.-Y., Liu, L., McEachern, D., Przybranowski, S., Wang, M., Stuckey, J., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00506 · Cited by 281 · see citing works

Chemically Induced Degradation of Sirtuin 2 (Sirt2) by a Proteolysis Targeting Chimera (PROTAC) Based on Sirtuin Rearranging Ligands (SirReals)

Schiedel, M., Herp, D., Hammelmann, S., Swyter, S., Lehotzky, A., Robaa, D., Oláh, J., Ovádi, J., Sippl, W., & Jung, M. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01872 · Cited by 275 · see citing works

Identification and Characterization of Von Hippel-Lindau-Recruiting Proteolysis Targeting Chimeras (PROTACs) of TANK-Binding Kinase 1

Crew, A. P., Raina, K., Dong, H., Qian, Y., Wang, J., Vigil, D., Serebrenik, Y. V., Hamman, B. D., Morgan, A., Ferraro, C., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00635 · Cited by 257 · see citing works

Small-Molecule Modulation of Protein Homeostasis.

Burslem, G., & Crews, C. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00077 · Cited by 256 · see citing works

In Vivo Knockdown of Pathogenic Proteins via Specific and Nongenetic Inhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers (SNIPERs)

Ohoka, N., Okuhira, K., Ito, M., Nagai, K., Shibata, N., Hattori, T., Ujikawa, O., Shimokawa, K., Sano, O., Koyama, R., et al. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.768853 · Cited by 240 · see citing works

Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5

Sebastiano, M. R., Doak, B. C., Backlund, M., Poongavanam, V., Over, B., Ermondi, G., Caron, G., Matsson, P., & Kihlberg, J. O. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00347 · Cited by 238 · see citing works

ADME Evaluation in Drug Discovery. 7. Prediction of Oral Absorption by Correlation and Classification

Hou, T., Wang, J., Zhang, W., & Xu, X. (2006) · Journal of Chemical Information and Modeling · doi:10.1021/ci600343x · Cited by 234 · see citing works

PROTACs: An Emerging Targeting Technique for Protein Degradation in Drug Discovery

Gu, S., Cui, D., Chen, X., Xiong, X., & Zhao, Y. (2018) · BioEssays · doi:10.1002/bies.201700247 · Cited by 231 · see citing works

Proteolysis-Targeting Chimeras: Induced Protein Degradation as a Therapeutic Strategy

Ottis, P., & Crews, C. M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.6b01068 · Cited by 227 · see citing works

Impact of Target Warhead and Linkage Vector on Inducing Protein Degradation: Comparison of Bromodomain and Extra-Terminal (BET) Degraders Derived from Triazolodiazepine (JQ1) and Tetrahydroquinoline (I-BET726) BET Inhibitor Scaffolds

Chan, K.-H., Zengerle, M., Testa, A., & Ciulli, A. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01912 · Cited by 222 · see citing works

Chemically induced degradation of CDK9 by a proteolysis targeting chimera (PROTAC)

Robb, C. M., Contreras, J. I., Kour, S., Taylor, M., Abid, M., Sonawane, Y. A., Zahid, M., Murry, D. J., Natarajan, A., & Rana, S. (2017) · Chemical Communications · doi:10.1039/c7cc03879h · Cited by 221 · see citing works

A “Click Chemistry Platform” for the Rapid Synthesis of Bispecific Molecules for Inducing Protein Degradation

Wurz, R. P., Dellamaggiore, K., Dou, H., Javier, N., LO, M. M. ‐., McCarter, J. D., Mohl, D. A., Sastri, C. E., Lipford, J. R., & Cee, V. J. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01781 · Cited by 217 · see citing works

Structural and conformational determinants of macrocycle cell permeability

Over, B., Matsson, P., Tyrchan, C., Artursson, P., Doak, B. C., Foley, M. A., Hilgendorf, C., Johnston, S. E., Lee, M. D., Lewis, R. J., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2203 · Cited by 209 · see citing works

CRISPR-Cas9: a new and promising player in gene therapy

Xiao-Jie, L., Hui-Ying, X., Zun-Ping, K., Jin-Lian, C., & Li-Juan, J. (2015) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2014-102968 · Cited by 200 · see citing works

Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

Powell, C. E., Gao, Y., Tan, L., Donovan, K. A., Nowak, R. P., Loehr, A., Bahcall, M., Fischer, E. S., Jänne, P. A., George, R. E., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01655 · Cited by 198 · see citing works

Development of the first small molecule histone deacetylase 6 (HDAC6) degraders

Yang, K., Song, Y., Xie, H., Wu, H., Wu, Y.-T., Leisten, E. D., & Tang, W. (2018) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.05.057 · Cited by 190 · see citing works

Modulating PCAF/GCN5 Immune Cell Function through a PROTAC Approach

Bassi, Z. I., Fillmore, M. C., Miah, A. H., Chapman, T. D., Maller, C., Roberts, E. J., Davis, L. C., Lewis, D. E., Galwey, N. W., Waddington, K. E., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00705 · Cited by 186 · see citing works

EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides

Goetz, G. H., Philippe, L., & Shapiro, M. J. (2014) · ACS Medicinal Chemistry Letters · doi:10.1021/ml500239m · Cited by 160 · see citing works

Development of Protein Degradation Inducers of Androgen Receptor by Conjugation of Androgen Receptor Ligands and Inhibitor of Apoptosis Protein Ligands

Shibata, N., Nagai, K., Morita, Y., Ujikawa, O., Ohoka, N., Hattori, T., Koyama, R., Sano, O., Imaeda, Y., Nara, H., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00168 · Cited by 147 · see citing works

First targeted protein degrader hits the clinic

Mullard, A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/d41573-019-00043-6 · Cited by 146 · see citing works

Chiral Inversion and Hydrolysis of Thalidomide: Mechanisms and Catalysis by Bases and Serum Albumin, and Chiral Stability of Teratogenic Metabolites

Reist, M., Carrupt, P., Francotte, E. R., & Testa, B. (1998) · Chemical Research in Toxicology · doi:10.1021/tx9801817 · Cited by 145 · see citing works

Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

McCoull, W., Cheung, T., Anderson, E., Barton, P., Burgess, J., Byth, K., Cao, Q., Castaldi, M. P., Chen, H., Chiarparin, E., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00698 · Cited by 139 · see citing works

Structural basis of thalidomide enantiomer binding to cereblon

Mori, T., Ito, T., Liu, S., Ando, H., Sakamoto, S., Yamaguchi, Y., Tokunaga, E., Shibata, N., Handa, H., & Hakoshima, T. (2018) · Scientific Reports · doi:10.1038/s41598-018-19202-7 · Cited by 131 · see citing works

Absorption, metabolism and excretion of [14C]pomalidomide in humans following oral administration

Hoffmann, M., Kasserra, C., Reyes, J., Schafer, P., Kosek, J., Capone, L., Parton, A., Kim-Kang, H., Surapaneni, S., & Kumar, G. (2013) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-012-2040-6 · Cited by 121 · see citing works

A chemical approach for global protein knockdown from mice to non-human primates

Sun, X., Wang, J., Yao, X., Zheng, W., Mao, Y., Lan, T., Wang, L., Sun, Y., Zhang, X., Zhao, Q., et al. (2019) · Cell Discovery · doi:10.1038/s41421-018-0079-1 · Cited by 118 · see citing works

Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation

Ohoka, N., Morita, Y., Nagai, K., Shimokawa, K., Ujikawa, O., Fujimori, I., Ito, M., Hayase, Y., Okuhira, K., Shibata, N., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001091 · Cited by 105 · see citing works

Phthalimide conjugations for the degradation of oncogenic PI3K

Li, W., Gao, C., Zhao, L., Yuan, Z., Chen, Y., & Jiang, Y. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.03.066 · Cited by 105 · see citing works

Oral Absorption, Intestinal Metabolism and Human Oral Bioavailability

El‐Kattan, A. F., & Varm, M. (2012) · InTech eBooks · doi:10.5772/31087 · Cited by 104 · see citing works

Peptide blockade of HIFα degradation modulates cellular metabolism and angiogenesis

Willam, C., Masson, N., Tian, Y., Mahmood, S., Wilson, M. I., Bicknell, R., Eckardt, K., Maxwell, P. H., Ratcliffe, P. J., & Pugh, C. W. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.162119399 · Cited by 104 · see citing works

Opportunities and guidelines for discovery of orally absorbed drugs in beyond rule of 5 space

Poongavanam, V., Doak, B. C., & Kihlberg, J. O. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.05.010 · Cited by 98 · see citing works

Development of Highly Potent and Selective Steroidal Inhibitors and Degraders of CDK8

Hatcher, J. M., Wang, E. S., Johannessen, L. H., Kwiatkowski, N. P., Sim, T., & Gray, N. S. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.8b00011 · Cited by 94 · see citing works

Demonstrating In-Cell Target Engagement Using a Pirin Protein Degradation Probe (CCT367766)

Chessum, N. E. A., Sharp, S. Y., Caldwell, J., Pasqua, E., Wilding, B., Colombano, G., Collins, I., Özer, B., Richards, M., Rowlands, M., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01406 · Cited by 90 · see citing works

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

Practical application of ligand efficiency metrics in lead optimisation

Scott, J. S., & Waring, M. J. (2018) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2018.04.004 · Cited by 54 · see citing works

Improvements in Solubility and Stability of Thalidomide upon Complexation with Hydroxypropyl-β-Cyclodextrin

Krenn, M., Gamcsik, M. P., Vogelsang, G. B., et al. (1992) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600810719 · Cited by 46 · see citing works

Experimental Lipophilicity for Beyond Rule of 5 Compounds

Ermondi, G., Vallaro, M., Goetz, G. H., et al. (2019) · Future Drug Discovery · doi:10.4155/fdd-2019-0002 · Cited by 38 · see citing works

LC–MS/MS and chiroptical spectroscopic analyses of multidimensional metabolic systems of chiral thalidomide and its derivatives

Ogino, Y., Tanaka, M., Shimozawa, T., et al. (2017) · Chirality · doi:10.1002/chir.22683 · Cited by 7 · see citing works

Targeted protein degradation: expanding the toolbox

Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works

Protein degraders enter the clinic — a new approach to cancer therapy

Chirnomas, D., Hornberger, K. R., & Crews, C. M. (2023) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00736-3 · Cited by 658 · see citing works

Development of targeted protein degradation therapeutics

Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489 · see citing works

Current strategies for the design of PROTAC linkers: a critical review

Troup, R. I., Fallan, C., & Baud, M. G. J. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00018 · Cited by 424 · see citing works

Molecular Glues for Targeted Protein Degradation: From Serendipity to Rational Discovery

Dong, G., Ding, Y., He, S., & Sheng, C. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00895 · Cited by 369 · see citing works

Proteolysis‐targeting chimeras in drug development: A safety perspective

Moreau, K., Coen, M., Zhang, A. X., Pachl, F., Castaldi, M. P., Dahl, G., Boyd, H., Scott, C., & Newham, P. (2020) · British Journal of Pharmacology · doi:10.1111/bph.15014 · Cited by 229 · see citing works

PROTAC-DB: an online database of PROTACs

Weng, G., Shen, C., Cao, D., Gao, J., Dong, X., He, Q., Yang, B., Li, D., Wu, J., & Hou, T. (2021) · Nucleic Acids Research · doi:10.1093/nar/gkaa807 · Cited by 219 · see citing works

Solution Conformations Shed Light on PROTAC Cell Permeability

Atilaw, Y., Poongavanam, V., Svensson Nilsson, C., Nguyen, D., Giese, A., Meibom, D., Erdelyi, M., & Kihlberg, J. (2021) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00556 · Cited by 208 · see citing works

Antibody Conjugation of a Chimeric BET Degrader Enables <i>in vivo</i> Activity

Pillow, T. H., Adhikari, P., Blake, R. A., Chen, J., Del Rosario, G., Deshmukh, G., Figueroa, I., Gascoigne, K. E., Kamath, A. V., Kaufman, S., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.201900497 · Cited by 216 · see citing works

RNA‐PROTACs: Degraders of RNA‐Binding Proteins

Ghidini, A., Cléry, A., Halloy, F., Allain, F. H. T., & Hall, J. (2021) · Angewandte Chemie International Edition · doi:10.1002/anie.202012330 · Cited by 197 · see citing works

Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy

Dragovich, P. S., Pillow, T. H., Blake, R. A., Sadowsky, J. D., Adaligil, E., Adhikari, P., Chen, J., Corr, N., dela Cruz-Chuh, J., Del Rosario, G., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01846 · Cited by 174 · see citing works

bioPROTACs as versatile modulators of intracellular therapeutic targets including proliferating cell nuclear antigen (PCNA)

Lim, S., Khoo, R., Peh, K. M., Teo, J., Chang, S. C., Ng, S., Beilhartz, G. L., Melnyk, R. A., Johannes, C. W., Brown, C. J., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1920251117 · Cited by 170 · see citing works

Improved Accuracy for Modeling PROTAC-Mediated Ternary Complex Formation and Targeted Protein Degradation <i>via</i> New <i>In Silico</i> Methodologies

Drummond, M. L., Henry, A., Li, H., & Williams, C. I. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00897 · Cited by 166 · see citing works

Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties

Dragovich, P. S., Pillow, T. H., Blake, R. A., Sadowsky, J. D., Adaligil, E., Adhikari, P., Bhakta, S., Blaquiere, N., Chen, J., dela Cruz-Chuh, J., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01845 · Cited by 152 · 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

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

Steinebach, C., Ng, Y. L. D., Sosič, I., Lee, C.-S., Chen, S., Lindner, S., Vu, L. P., Bricelj, A., Haschemi, R., Monschke, M., et al. (2020) · Chemical Science · doi:10.1039/d0sc00167h · Cited by 148 · see citing works

Integrative Modeling of PROTAC-Mediated Ternary Complexes

Weng, G., Li, D., Kang, Y., & Hou, T. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c01576 · Cited by 130 · see citing works

Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)

Dragovich, P. S., Adhikari, P., Blake, R. A., Blaquiere, N., Chen, J., Cheng, Y.-X., den Besten, W., Han, J., Hartman, S. J., He, J., et al. (2020) · Bioorganic &amp; Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126907 · Cited by 120 · see citing works

Bifunctional chemical probes inducing protein–protein interactions

Maniaci, C., & Ciulli, A. (2019) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2019.07.003 · Cited by 100 · see citing works

PROTAC degraders as chemical probes for studying target biology and target validation

Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98 · see citing works

Trends in Molecular Properties, Bioavailability, and Permeability across the Bayer Compound Collection: Miniperspective

O’ Donovan, D. H., De Fusco, C., Kuhnke, L., & Reichel, A. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01577 · Cited by 83 · see citing works

PROTAC Cell Permeability and Oral Bioavailability: A Journey Into Uncharted Territory

Poongavanam, V., & Kihlberg, J. (2022) · Future Medicinal Chemistry · doi:10.4155/fmc-2021-0208 · Cited by 72 · see citing works

Monomeric Targeted Protein Degraders

Hanan, E. J., Liang, J., Wang, X., Blake, R. A., Blaquiere, N., & Staben, S. T. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00093 · Cited by 69 · see citing works

Design, Synthesis, and Biological Evaluation of IRAK4-Targeting PROTACs

Chen, Y., Ning, Y., Bai, G., Tong, L., Zhang, T., Zhou, J., Zhang, H., Xie, H., Ding, J., & Duan, W. (2021) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00474 · Cited by 49 · see citing works

Atomic-Resolution Prediction of Degrader-mediated Ternary Complex Structures by Combining Molecular Simulations with Hydrogen Deuterium Exchange

Dixon, T., MacPherson, D., Mostofian, B., Dauzhenka, T., Lotz, S., McGee, D., Shechter, S., Shrestha, U. R., Wiewiora, R., McDargh, Z. A., et al. (2021) · doi:10.1101/2021.09.26.461830 · Cited by 7 · see citing works

Destruction of DNA-binding proteins by programmable O’PROTAC: Oligonucleotide-based PROTAC

Shao, J., Yan, Y., Ding, D., Wang, D., He, Y., Pan, Y., Yan, W., Kharbanda, A., Li, H.-Y., & Huang, H. (2021) · doi:10.1101/2021.03.08.434493 · Cited by 2 · see citing works

Fragment-based screening with natural products for novel anti-parasitic disease drug discovery

Liu, M., & Quinn, R. J. (2019) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2019.1653849 · Cited by 29 · see citing works

Chemical Space Mimicry for Drug Discovery

Yuan, W., Jiang, D., Nambiar, D. K., Liew, L. P., Hay, M. P., Bloomstein, J. D., Lu, P., Turner, B. E., Le, Q., Tibshirani, R. J., et al. (2017) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.6b00754 · Cited by 100 · see citing works

Fragment‐based drug discovery—the importance of high‐quality molecule libraries

Bon, M., Bilsland, A. E., Bower, J. F., & McAulay, K. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13277 · Cited by 153 · see citing works

The Growing Importance of Chirality in 3D Chemical Space Exploration and Modern Drug Discovery Approaches for Hit-ID

Silvestri, I. P., & Colbon, P. J. J. (2021) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.1c00251 · Cited by 85 · see citing works

Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (CyreneTM)

Dekker, T., Harteveld, J. W., Wágner, G., de Vries, M. C. M., Custers, H., van de Stolpe, A. C., de Esch, I. J. P., & Wijtmans, M. (2023) · Molecules · doi:10.3390/molecules28041777 · Cited by 13 · see citing works