Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers
Abstract
:1. Introduction
2. Distinct Roles of KRAS in Tumorigenesis and Attempts to Inhibit KRAS Signaling
2.1. Direct Inhibition of RAS
2.2. Indirect Inhibition of RAS
2.2.1. Inhibitors of Guanine Nucleotide Exchange Cycle
2.2.2. Inhibitors of RAS Processing
2.2.3. Inhibitors of RAS Effector Proteins
3. Targeted Protein Degraders
3.1. Direct KRAS Degrader
3.2. Degraders of GEFs
3.2.1. RAS Degrader Using the Protein–Protein Interaction (PPI) between the RAS and Son of Sevenless I (SOS1) Interaction
3.2.2. SHP2 Protein Degrader
3.3. RAF Degrader
3.4. MEK1/2 Degrader
3.5. ERK Degraders
4. Perspectives and Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Uprety, D.; Adjei, A.A. KRAS: From undruggable to a druggable Cancer Target. Cancer Treat. Rev. 2020, 89, 102070. [Google Scholar] [CrossRef]
- Hobbs, G.A.; Der, C.J.; Rossman, K.L. RAS isoforms and mutations in cancer at a glance. J. Cell Sci. 2016, 129, 1287–1292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vasan, N.; Baselga, J.; Hyman, D.M. A view on drug resistance in cancer. Nature 2019, 575, 299–309. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferrer, I.; Zugazagoitia, J.; Herbertz, S.; John, W.; Paz-Ares, L.; Schmid-Bindert, G. KRAS-Mutant non-small cell lung cancer: From biology to therapy. Lung Cancer 2018, 124, 53–64. [Google Scholar] [CrossRef] [Green Version]
- Dinu, D.; Dobre, M.; Panaitescu, E.; Bîrlă, R.; Iosif, C.; Hoara, P.; Caragui, A.; Boeriu, M.; Constantinoiu, S.; Ardeleanu, C. Prognostic significance of KRAS gene mutations in colorectal cancer—preliminary study. J. Med. Life 2014, 7, 581–587. [Google Scholar] [PubMed]
- Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer. 2003, 3, 11–22. [Google Scholar] [CrossRef] [PubMed]
- Pantsar, T. The current understanding of KRAS protein structure and dynamics. Comput. Struct. Biotechnol. J. 2020, 18, 189–198. [Google Scholar] [CrossRef]
- Moore, A.R.; Rosenberg, S.C.; McCormick, F.; Malek, S. RAS-targeted therapies: Is the undruggable drugged? Nat. Rev. Drug Discov. 2020, 19, 533–552. [Google Scholar] [CrossRef] [PubMed]
- Taveras, A.G.; Remiszewski, S.W.; Doll, R.J.; Cesarz, D.; Huang, E.C.; Kirschmeier, P.; Pramanik, B.N.; Snow, M.E.; Wang, Y.S.; del Rosario, J.D.; et al. Ras oncoprotein inhibitors: The discovery of potent, ras nucleotide exchange inhibitors and the structural determination of a drug-protein complex. Biorg. Med. Chem. 1997, 5, 125–133. [Google Scholar] [CrossRef]
- Welsch, M.E.; Kaplan, A.; Chambers, J.M.; Stokes, M.E.; Bos, P.H.; Zask, A.; Zhang, Y.; Sanchez-Martin, M.; Badgley, M.A.; Huang, C.S.; et al. Multivalent Small-Molecule Pan-RAS Inhibitors. Cell 2017, 168, 878–889.e829. [Google Scholar] [CrossRef] [Green Version]
- Cruz-Migoni, A.; Canning, P.; Quevedo, C.E.; Bataille, C.J.R.; Bery, N.; Miller, A.; Russell, A.J.; Phillips, S.E.V.; Carr, S.B.; Rabbitts, T.H. Structure-based development of new RAS-effector inhibitors from a combination of active and inactive RAS-binding compounds. Proc. Natl. Acad. Sci. USA 2019, 116, 2545–2550. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McCarthy, M.J.; Pagba, C.V.; Prakash, P.; Naji, A.K.; van der Hoeven, D.; Liang, H.; Gupta, A.K.; Zhou, Y.; Cho, K.-J.; Hancock, J.F.; et al. Discovery of High-Affinity Noncovalent Allosteric KRAS Inhibitors That Disrupt Effector Binding. ACS Omega 2019, 4, 2921–2930. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kessler, D.; Gmachl, M.; Mantoulidis, A.; Martin, L.J.; Zoephel, A.; Mayer, M.; Gollner, A.; Covini, D.; Fischer, S.; Gerstberger, T.; et al. Drugging an undruggable pocket on KRAS. Proc. Natl. Acad. Sci. USA 2019, 116, 15823–15829. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ostrem, J.M.; Peters, U.; Sos, M.L.; Wells, J.A.; Shokat, K.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013, 503, 548–551. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Canon, J.; Rex, K.; Saiki, A.Y.; Mohr, C.; Cooke, K.; Bagal, D.; Gaida, K.; Holt, T.; Knutson, C.G.; Koppada, N.; et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 2019, 575, 217–223. [Google Scholar] [CrossRef] [PubMed]
- Hallin, J.; Engstrom, L.D.; Hargis, L.; Calinisan, A.; Aranda, R.; Briere, D.M.; Sudhakar, N.; Bowcut, V.; Baer, B.R.; Ballard, J.A.; et al. The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2020, 10, 54–71. [Google Scholar] [CrossRef] [Green Version]
- Goebel, L.; Müller, M.P.; Goody, R.S.; Rauh, D. KRasG12C inhibitors in clinical trials: A short historical perspective. RSC Med. Chem. 2020, 11, 760–770. [Google Scholar] [CrossRef]
- Janes, M.R.; Zhang, J.; Li, L.-S.; Hansen, R.; Peters, U.; Guo, X.; Chen, Y.; Babbar, A.; Firdaus, S.J.; Darjania, L.; et al. Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell 2018, 172, 578–589.e517. [Google Scholar] [CrossRef] [Green Version]
- Nagasaka, M.; Potugari, B.; Nguyen, A.; Sukari, A.; Azmi, A.S.; Ou, S.-H.I. KRAS Inhibitors- yes but what next? Direct targeting of KRAS-vaccines, adoptive T cell therapy and beyond. Cancer Treat. Rev. 2021, 101, 102309. [Google Scholar] [CrossRef]
- Dunnett-Kane, V.; Nicola, P.; Blackhall, F.; Lindsay, C. Mechanisms of Resistance to KRASG12C Inhibitors. Cancers 2021, 13, 151. [Google Scholar] [CrossRef]
- Hunter, J.C.; Manandhar, A.; Carrasco, M.A.; Gurbani, D.; Gondi, S.; Westover, K.D. Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol. Cancer Res. 2015, 13, 1325. [Google Scholar] [CrossRef] [Green Version]
- Zhang, Z.; Gao, R.; Hu, Q.; Peacock, H.; Peacock, D.M.; Dai, S.; Shokat, K.M.; Suga, H. GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf. ACS Cent. Sci. 2020, 6, 1753–1761. [Google Scholar] [CrossRef]
- Gu, S.; Sayad, A.; Chan, G.; Yang, W.; Lu, Z.; Virtanen, C.; Van Etten, R.A.; Neel, B.G. SHP2 is required for BCR-ABL1-induced hematologic neoplasia. Leukemia 2018, 32, 203–213. [Google Scholar] [CrossRef]
- LaMarche, M.J.; Acker, M.; Argintaru, A.; Bauer, D.; Boisclair, J.; Chan, H.; Chen, C.H.-T.; Chen, Y.-N.; Chen, Z.; Deng, Z.; et al. Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer. J. Med. Chem. 2020, 63, 13578–13594. [Google Scholar] [CrossRef]
- Song, Z.; Wang, M.; Ge, Y.; Chen, X.-P.; Xu, Z.; Sun, Y.; Xiong, X.-F. Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies. Acta Pharm. Sin. B 2021, 11, 13–29. [Google Scholar] [CrossRef] [PubMed]
- Gort, E.; Johnson, M.L.; Hwang, J.J.; Pant, S.; Dünzinger, U.; Riemann, K.; Kitzing, T.; Janne, P.A. A phase I, open-label, dose-escalation trial of BI 1701963 as monotherapy and in combination with trametinib in patients with KRAS mutated advanced or metastatic solid tumors. J. Clin. Oncol. 2020, 38, TPS3651. [Google Scholar] [CrossRef]
- Chen, H.; Libring, S.; Ruddraraju, K.V.; Miao, J.; Solorio, L.; Zhang, Z.-Y.; Wendt, M.K. SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer. Oncogene 2020, 39, 7166–7180. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.-N.P.; LaMarche, M.J.; Chan, H.M.; Fekkes, P.; Garcia-Fortanet, J.; Acker, M.G.; Antonakos, B.; Chen, C.H.-T.; Chen, Z.; Cooke, V.G.; et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 2016, 535, 148–152. [Google Scholar] [CrossRef]
- Bendell, J.; Ulahannan, S.; Koczywas, M.; Brahmer, J.; Capasso, A.; Eckhardt, S.G.; Gordon, M.; McCoach, C.; Nagasaka, M.; Ng, K.; et al. Intermittent dosing of RMC-4630, a potent, selective inhibitor of SHP2, combined with the MEK inhibitor cobimetinib, in a phase 1b/2 clinical trial for advanced solid tumors with activating mutations of RAS signaling. Eur. J. Cancer 2020, 138, S8–S9. [Google Scholar] [CrossRef]
- End, D.W.; Smets, G.; Todd, A.V.; Applegate, T.L.; Fuery, C.J.; Angibaud, P.; Venet, M.; Sanz, G.; Poignet, H.; Skrzat, S.; et al. Characterization of the Antitumor Effects of the Selective Farnesyl Protein Transferase Inhibitor R115777 in Vivo and in Vitro. Cancer Res. 2001, 61, 131–137. [Google Scholar] [PubMed]
- Gilardi, M.; Wang, Z.; Proietto, M.; Chillà, A.; Calleja-Valera, J.L.; Goto, Y.; Vanoni, M.; Janes, M.R.; Mikulski, Z.; Gualberto, A.; et al. Tipifarnib as a Precision Therapy for HRAS-Mutant Head and Neck Squamous Cell Carcinomas. Mol. Cancer Ther. 2020, 19, 1784–1796. [Google Scholar] [CrossRef]
- Xie, C.; Li, Y.; Li, L.-L.; Fan, X.-X.; Wang, Y.-W.; Wei, C.-L.; Liu, L.; Leung, E.L.-H.; Yao, X.-J. Identification of a New Potent Inhibitor Targeting KRAS in Non-small Cell Lung Cancer Cells. Front. Pharmacol. 2017, 8, 823. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ramakrishnan, V.; Timm, M.; Haug, J.L.; Kimlinger, T.K.; Wellik, L.E.; Witzig, T.E.; Rajkumar, S.V.; Adjei, A.A.; Kumar, S. Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene 2010, 29, 1190–1202. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karoulia, Z.; Gavathiotis, E.; Poulikakos, P.I. New perspectives for targeting RAF kinase in human cancer. Nat. Rev. Cancer. 2017, 17, 676–691. [Google Scholar] [CrossRef]
- Pant, S.; Bendell, J.C.; Sullivan, R.J.; Shapiro, G.; Millward, M.; Mi, G.; Yuen, E.; Willard, M.D.; Wang, D.; Joseph, S.; et al. A phase I dose escalation (DE) study of ERK inhibitor, LY3214996, in advanced (adv) cancer (CA) patients (pts). J. Clin. Oncol. 2019, 37, 3001. [Google Scholar] [CrossRef]
- Buchbinder, E.I.; Cohen, J.V.; Haq, R.; Hodi, F.S.; Lawrence, D.P.; Giobbie-Hurder, A.; Knoerzer, D.; Sullivan, R.J. A phase II study of ERK inhibition by ulixertinib (BVD-523) in metastatic uveal melanoma. J. Clin. Oncol. 2020, 38, 10036. [Google Scholar] [CrossRef]
- Moschos, S.J.; Sullivan, R.J.; Hwu, W.-J.; Ramanathan, R.K.; Adjei, A.A.; Fong, P.C.; Shapira-Frommer, R.; Tawbi, H.A.; Rubino, J.; Rush, T.S., III; et al. Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight 2018, 3, e92352. [Google Scholar] [CrossRef]
- Mei, B.; Zhu, L.; Guo, Y.; Wu, T.; Ren, P.; Deng, X. Solid Form Selection and Process Development of KO-947 Drug Substances. Org. Process. Res. Dev. 2021, 25, 1637–1647. [Google Scholar] [CrossRef]
- Bond, M.J.; Chu, L.; Nalawansha, D.A.; Li, K.; Crews, C.M. Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs. ACS Cent. Sci. 2020, 6, 1367–1375. [Google Scholar] [CrossRef]
- Zeng, M.; Xiong, Y.; Safaee, N.; Nowak, R.P.; Donovan, K.A.; Yuan, C.J.; Nabet, B.; Gero, T.W.; Feru, F.; Li, L.; et al. Exploring Targeted Degradation Strategy for Oncogenic KRASG12C. Cell Chem. Biol. 2020, 27, 19–31.e16. [Google Scholar] [CrossRef]
- Pudewell, S.; Wittich, C.; Kazemein Jasemi, N.S.; Bazgir, F.; Ahmadian, M.R. Accessory proteins of the RAS-MAPK pathway: Moving from the side line to the front line. Commun. Biol. 2021, 4, 696. [Google Scholar] [CrossRef]
- Imanishi, S.; Huang, L.; Itakura, S.; Ishizaka, M.; Tsukamoto, M.; Saito, M.; Iwasaki, Y.; Yamaguchi, T.; Miyamoto-Sato, E. In Vivo KRAS G12D/V Degradation Mediated by CANDDY Using a Modified Proteasome Inhibitor. bioRxiv 2021. [Google Scholar] [CrossRef]
- Wang, M.; Lu, J.; Wang, M.; Yang, C.-Y.; Wang, S. Discovery of SHP2-D26 as a First, Potent, and Effective PROTAC Degrader of SHP2 Protein. J. Med. Chem. 2020, 63, 7510–7528. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Wang, Z.; Pei, Y.; Song, N.; Xu, L.; Feng, B.; Wang, H.; Luo, X.; Hu, X.; Qiu, X.; et al. Discovery of thalidomide-based PROTAC small molecules as the highly efficient SHP2 degraders. Eur. J. Med. Chem. 2021, 218, 113341. [Google Scholar] [CrossRef] [PubMed]
- Zheng, M.; Liu, Y.; Wu, C.; Yang, K.; Wang, Q.; Zhou, Y.; Chen, L.; Li, H. Novel PROTACs for degradation of SHP2 protein. Bioorg. Chem. 2021, 110, 104788. [Google Scholar] [CrossRef] [PubMed]
- Vemulapalli, V.; Donovan, K.A.; Seegar, T.C.M.; Rogers, J.M.; Bae, M.; Lumpkin, R.J.; Cao, R.; Henke, M.T.; Fischer, E.S.; Cuny, G.D.; et al. Targeted Degradation of the Oncogenic Phosphatase SHP2. Biochemistry 2021, 60, 2593–2609. [Google Scholar] [CrossRef]
- Nichols, R.J.; Haderk, F.; Stahlhut, C.; Schulze, C.J.; Hemmati, G.; Wildes, D.; Tzitzilonis, C.; Mordec, K.; Marquez, A.; Romero, J.; et al. RAS nucleotide cycling underlies the SHP2 phosphatase dependence of mutant BRAF-, NF1- and RAS-driven cancers. Nat. Cell Biol. 2018, 20, 1064–1073. [Google Scholar] [CrossRef]
- Davies, H.; Bignell, G.R.; Cox, C.; Stephens, P.; Edkins, S.; Clegg, S.; Teague, J.; Woffendin, H.; Garnett, M.J.; Bottomley, W.; et al. Mutations of the BRAF gene in human cancer. Nature 2002, 417, 949–954. [Google Scholar] [CrossRef]
- Alabi, S.; Jaime-Figueroa, S.; Yao, Z.; Gao, Y.; Hines, J.; Samarasinghe, K.T.G.; Vogt, L.; Rosen, N.; Crews, C.M. Mutant-selective degradation by BRAF-targeting PROTACs. Nat. Commun. 2021, 12, 920. [Google Scholar] [CrossRef]
- Chen, H.; Chen, F.; Pei, S.; Gou, S. Pomalidomide hybrids act as proteolysis targeting chimeras: Synthesis, anticancer activity and B-Raf degradation. Bioorg. Chem. 2019, 87, 191–199. [Google Scholar] [CrossRef]
- Wang, C.; Wang, H.; Zheng, C.; Liu, Z.; Gao, X.; Xu, F.; Niu, Y.; Zhang, L.; Xu, P. Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer. Eur. J. Med. Chem. 2021, 218, 113386. [Google Scholar] [CrossRef] [PubMed]
- Wei, J.; Hu, J.; Wang, L.; Xie, L.; Jin, M.S.; Chen, X.; Liu, J.; Jin, J. Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader. J. Med. Chem. 2019, 62, 10897–10911. [Google Scholar] [CrossRef] [PubMed]
- Hu, J.; Wei, J.; Yim, H.; Wang, L.; Xie, L.; Jin, M.S.; Kabir, M.; Qin, L.; Chen, X.; Liu, J.; et al. Potent and Selective Mitogen-Activated Protein Kinase Kinase 1/2 (MEK1/2) Heterobifunctional Small-molecule Degraders. J. Med. Chem. 2020, 63, 15883–15905. [Google Scholar] [CrossRef]
- Vollmer, S.; Cunoosamy, D.; Lv, H.; Feng, H.; Li, X.; Nan, Z.; Yang, W.; Perry, M.W.D. Design, Synthesis, and Biological Evaluation of MEK PROTACs. J. Med. Chem. 2020, 63, 157–162. [Google Scholar] [CrossRef]
- Dix, M.M.; Simon, G.M.; Cravatt, B.F. Global Mapping of the Topography and Magnitude of Proteolytic Events in Apoptosis. Cell 2008, 134, 679–691. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mahrus, S.; Trinidad, J.C.; Barkan, D.T.; Sali, A.; Burlingame, A.L.; Wells, J.A. Global Sequencing of Proteolytic Cleavage Sites in Apoptosis by Specific Labeling of Protein N Termini. Cell 2008, 134, 866–876. [Google Scholar] [CrossRef] [Green Version]
- Peh, J.; Boudreau, M.W.; Smith, H.M.; Hergenrother, P.J. Overcoming Resistance to Targeted Anticancer Therapies through Small-Molecule-Mediated MEK Degradation. Cell Chem. Biol. 2018, 25, 996–1005.e1004. [Google Scholar] [CrossRef]
- Lebraud, H.; Wright, D.J.; Johnson, C.N.; Heightman, T.D. Protein Degradation by In-Cell Self-Assembly of Proteolysis Targeting Chimeras. ACS Cent. Sci. 2016, 2, 927–934. [Google Scholar] [CrossRef] [Green Version]
- Burslem, G.M.; Schultz, A.R.; Bondeson, D.P.; Eide, C.A.; Savage Stevens, S.L.; Druker, B.J.; Crews, C.M. Targeting BCR-ABL1 in Chronic Myeloid Leukemia by PROTAC-Mediated Targeted Protein Degradation. Cancer Res. 2019, 79, 4744–4753. [Google Scholar] [CrossRef]
- Qi, S.-M.; Dong, J.; Xu, Z.-Y.; Cheng, X.-D.; Zhang, W.-D.; Qin, J.-J. PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy. Front. Pharmacol. 2021, 12, 1124. [Google Scholar] [CrossRef]
- Sun, X.; Rao, Y. PROTACs as Potential Therapeutic Agents for Cancer Drug Resistance. Biochemistry 2020, 59, 240–249. [Google Scholar] [CrossRef] [PubMed]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Hyun, S.; Shin, D. Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers. Int. J. Mol. Sci. 2021, 22, 12142. https://doi.org/10.3390/ijms222212142
Hyun S, Shin D. Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers. International Journal of Molecular Sciences. 2021; 22(22):12142. https://doi.org/10.3390/ijms222212142
Chicago/Turabian StyleHyun, Soonsil, and Dongyun Shin. 2021. "Small-Molecule Inhibitors and Degraders Targeting KRAS-Driven Cancers" International Journal of Molecular Sciences 22, no. 22: 12142. https://doi.org/10.3390/ijms222212142