Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Targeting of SOS1: from SOS1 Activators to Proteolysis Targeting Chimeras

Author(s): Gerhard Hamilton*, Sandra Stickler and Barbara Rath

Volume 29, Issue 22, 2023

Published on: 27 April, 2023

Page: [1741 - 1746] Pages: 6

DOI: 10.2174/1381612829666230418114520

Price: $65

conference banner
Abstract

The most frequent mutated oncogene KRAS in lung cancer is targeted by KRAS G12C-directed drugs, such as Sotorasib and Adagrasib. Still, other alleles frequently expressed in pancreatic and colon cancer may be attacked indirectly by hitting the guanine nucleotide exchange factor (GEF) SOS1 that loads and activates KRAS. The first modulators of SOS1 were found to act as agonists and defined a hydrophobic pocket at the catalytic site. High throughput screenings resulted in the detection of SOS1 inhibitors Bay-293 and BI-3406 comprising amino quinazoline scaffolds optimized for binding to the pocket by various substituents. The first inhibitor, BI-1701963, is in clinical studies alone or in combination with a KRAS inhibitor, a MAPK inhibitor or chemotherapeutics. An optimized agonist, VUBI-1, shows activity against tumor cells by destructive overactivation of cellular signaling. This agonist was used to formulate a proteolysis targeting chimera (PROTAC), that labels SOS1 for degradation by proteasomal degradation through a linked VHL E3 ligase ligand. This PROTAC exhibited the highest SOS1-directed activity due to target destruction, recycling and removal of SOS1 as a scaffolding protein. Although other first PROTACs have entered clinical trials, each conjugate must be meticulously adapted as an efficient clinical drug.

Keywords: KRAS, SOS1, PROTAC, agonist, inhibitors, proteasome.

« Previous Next »
[1]
Lee JK, Sivakumar S, Schrock AB, et al. Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors. NPJ Precis Oncol 2022; 6(1): 91.
[http://dx.doi.org/10.1038/s41698-022-00334-z] [PMID: 36494601]
[2]
Timar J, Kashofer K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev 2020; 39(4): 1029-38.
[http://dx.doi.org/10.1007/s10555-020-09915-5] [PMID: 32725342]
[3]
Scheffzek K, Ahmadian MR, Kabsch W, et al. The Ras-RasGAP complex: Structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997; 277(5324): 333-9.
[http://dx.doi.org/10.1126/science.277.5324.333] [PMID: 9219684]
[4]
Vigil D, Cherfils J, Rossman KL, Der CJ. Ras superfamily GEFs and GAPs: Validated and tractable targets for cancer therapy? Nat Rev Cancer 2010; 10(12): 842-57.
[http://dx.doi.org/10.1038/nrc2960] [PMID: 21102635]
[5]
Zulfiqar B, Farooq A, Kanwal S, Asghar K. Immunotherapy and targeted therapy for lung cancer: Current status and future perspectives. Front Pharmacol 2022; 13: 1035171.
[http://dx.doi.org/10.3389/fphar.2022.1035171] [PMID: 36518665]
[6]
Ostrem JML, Shokat KM. Direct small-molecule inhibitors of KRAS: From structural insights to mechanism-based design. Nat Rev Drug Discov 2016; 15(11): 771-85.
[http://dx.doi.org/10.1038/nrd.2016.139] [PMID: 27469033]
[7]
Uprety D, Adjei AA. KRAS: From undruggable to a druggable cancer target. Cancer Treat Rev 2020; 89: 102070.
[http://dx.doi.org/10.1016/j.ctrv.2020.102070] [PMID: 32711246]
[8]
Bungaro M, Novello S, Passiglia F. Targeting KRASp.G12C mutation in advanced non-small cell lung cancer: A new era has begun. Curr Treat Options Oncol 2022; 23(12): 1699-720.
[http://dx.doi.org/10.1007/s11864-022-01033-4] [PMID: 36394791]
[9]
Hofmann MH, Gerlach D, Misale S, Petronczki M, Kraut N. Expanding the reach of precision oncology by drugging All KRAS mutants. Cancer Discov 2022; 12(4): 924-37.
[http://dx.doi.org/10.1158/2159-8290.CD-21-1331] [PMID: 35046095]
[10]
Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: Critical elements in the control of small G proteins. Cell 2007; 129(5): 865-77.
[http://dx.doi.org/10.1016/j.cell.2007.05.018] [PMID: 17540168]
[11]
Jiao D, Yang S. Overcoming resistance to drugs targeting KRAS mutation. Innovation 2020; 1(2): 100035.
[http://dx.doi.org/10.1016/j.xinn.2020.100035] [PMID: 32939510]
[12]
Kessler D, Gerlach D, Kraut N, McConnell DB. Targeting son of sevenless 1: The pacemaker of KRAS. Curr Opin Chem Biol 2021; 62: 109-18.
[http://dx.doi.org/10.1016/j.cbpa.2021.02.014] [PMID: 33848766]
[13]
Hofmann MH, Gmachl M, Ramharter J, et al. BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov 2021; 11(1): 142-57.
[http://dx.doi.org/10.1158/2159-8290.CD-20-0142] [PMID: 32816843]
[14]
Burns MC, Howes JE, Sun Q, et al. High-throughput screening identifies small molecules that bind to the RAS:SOS:RAS complex and perturb RAS signaling. Anal Biochem 2018; 548: 44-52.
[http://dx.doi.org/10.1016/j.ab.2018.01.025] [PMID: 29444450]
[15]
Burns MC, Sun Q, Daniels RN, et al. Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange. Proc Natl Acad Sci USA 2014; 111(9): 3401-6.
[http://dx.doi.org/10.1073/pnas.1315798111] [PMID: 24550516]
[16]
Evelyn CR, Duan X, Biesiada J, Seibel WL, Meller J, Zheng Y. Rational design of small molecule inhibitors targeting the Ras GEF, SOS1. Chem Biol 2014; 21(12): 1618-28.
[http://dx.doi.org/10.1016/j.chembiol.2014.09.018] [PMID: 25455859]
[17]
Hodges TR, Abbott JR, Little AJ, et al. Discovery and structure-based optimization of benzimidazole-derived activators of SOS1-mediated nucleotide exchange on RAS. J Med Chem 2018; 61(19): 8875-94.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01108] [PMID: 30205005]
[18]
Howes JE, Akan DT, Burns MC, Rossanese OW, Waterson AG, Fesik SW. Small molecule-mediated activation of RAS elicits biphasic modulation of phospho-ERK levels that are regulated through negative feedback on SOS1. Mol Cancer Ther 2018; 17(5): 1051-60.
[http://dx.doi.org/10.1158/1535-7163.MCT-17-0666] [PMID: 29440291]
[19]
Hillig RC, Sautier B, Schroeder J, et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc Natl Acad Sci USA 2019; 116(7): 2551-60.
[http://dx.doi.org/10.1073/pnas.1812963116] [PMID: 30683722]
[20]
Hillig RC, Bader B. Targeting RAS oncogenesis with SOS1 inhibitors. Adv Cancer Res 2022; 153: 169-203.
[http://dx.doi.org/10.1016/bs.acr.2021.07.001] [PMID: 35101230]
[21]
Overmeyer JH, Maltese WA. Death pathways triggered by activated Ras in cancer cells. Front Biosci 2011; 16(1): 1693-713.
[http://dx.doi.org/10.2741/3814] [PMID: 21196257]
[22]
Xu K, Park D, Magis AT, et al. Small molecule KRAS agonist for mutant KRAS cancer therapy. Mol Cancer 2019; 18(1): 85.
[http://dx.doi.org/10.1186/s12943-019-1012-4] [PMID: 30971271]
[23]
Kamioka Y, Yasuda S, Fujita Y, Aoki K, Matsuda M. Multiple decisive phosphorylation sites for the negative feedback regulation of SOS1 via ERK. J Biol Chem 2010; 285(43): 33540-8.
[http://dx.doi.org/10.1074/jbc.M110.135517] [PMID: 20724475]
[24]
Thompson SK, Buckl A, Dossetter AG, Griffen E, Gill A. Small molecule Son of Sevenless 1 (SOS1) inhibitors: A review of the patent literature. Expert Opin Ther Pat 2021; 31(12): 1189-204.
[http://dx.doi.org/10.1080/13543776.2021.1952984] [PMID: 34253125]
[25]
Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002; 277(48): 46265-72.
[http://dx.doi.org/10.1074/jbc.M207135200] [PMID: 12196540]
[26]
Yun CH, Boggon TJ, Li Y, et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: Mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 2007; 11(3): 217-27.
[http://dx.doi.org/10.1016/j.ccr.2006.12.017] [PMID: 17349580]
[27]
Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther 2012; 343(2): 342-50.
[http://dx.doi.org/10.1124/jpet.112.197756] [PMID: 22888144]
[28]
Nyíri K, Koppány G, Vértessy BG. Structure-based inhibitor design of mutant RAS proteins-a paradigm shift. Cancer Metastasis Rev 2020; 39(4): 1091-105.
[http://dx.doi.org/10.1007/s10555-020-09914-6] [PMID: 32715349]
[29]
Sarkar D, Olejniczak ET, Phan J, et al. Discovery of sulfonamide-derived agonists of SOS1-mediated nucleotide exchange on RAS using fragment-based methods. J Med Chem 2020; 63(15): 8325-37.
[http://dx.doi.org/10.1021/acs.jmedchem.0c00511] [PMID: 32673492]
[30]
Ketcham JM, Haling J, Khare S, et al. Design and discovery of MRTX0902, a potent, selective, brain-penetrant, and orally bioavailable inhibitor of the SOS1:KRAS protein-protein interaction. J Med Chem 2022; 65(14): 9678-90.
[http://dx.doi.org/10.1021/acs.jmedchem.2c00741] [PMID: 35833726]
[31]
Das D, Hong J. Recent advancements of 4-aminoquinazoline derivatives as kinase inhibitors and their applications in medicinal chemistry. Eur J Med Chem 2019; 170: 55-72.
[http://dx.doi.org/10.1016/j.ejmech.2019.03.004] [PMID: 30878832]
[32]
Li X, Pu W, Zheng Q, Ai M, Chen S, Peng Y. Proteolysis-targeting chimeras (PROTACs) in cancer therapy. Mol Cancer 2022; 21(1): 99.
[http://dx.doi.org/10.1186/s12943-021-01434-3] [PMID: 35410300]
[33]
Li JW, Zheng G, Kaye FJ, et al. PROTAC therapy as a new targeted therapy for lung cancer. Mol Ther 2022; S1525-0016(22): 00669-4.
[http://dx.doi.org/10.1016/j.ymthe.2022.11.011]
[34]
Diehl CJ, Ciulli A. Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders. Chem Soc Rev 2022; 51(19): 8216-57.
[http://dx.doi.org/10.1039/D2CS00387B] [PMID: 35983982]
[35]
Bondeson DP, Smith BE, Burslem GM, et al. Lessons in PROTAC design from selective degradation with a promiscuous warhead. Cell Chem Biol 2018; 25(1): 78-87.e5.
[http://dx.doi.org/10.1016/j.chembiol.2017.09.010] [PMID: 29129718]
[36]
Békés M, Langley DR, Crews CM. PROTAC targeted protein degraders: The past is prologue. Nat Rev Drug Discov 2022; 21(3): 181-200.
[http://dx.doi.org/10.1038/s41573-021-00371-6] [PMID: 35042991]
[37]
Bond MJ, Chu L, Nalawansha DA, Li K, Crews CM. Targeted degradation of oncogenic KRASG12C by VHL-recruiting PROTACs. ACS Cent Sci 2020; 6(8): 1367-75.
[http://dx.doi.org/10.1021/acscentsci.0c00411] [PMID: 32875077]
[38]
Poongavanam V, Atilaw Y, Siegel S, et al. Linker-dependent folding rationalizes PROTAC cell permeability. J Med Chem 2022; 65(19): 13029-40.
[http://dx.doi.org/10.1021/acs.jmedchem.2c00877] [PMID: 36170570]
[39]
Li Y, Li S, Wu H. Ubiquitination-Proteasome System (UPS) and autophagy two main protein degradation machineries in response to cell stress. Cells 2022; 11(5): 851.
[http://dx.doi.org/10.3390/cells11050851] [PMID: 35269473]
[40]
Yokoo H, Naganuma M, Oba M, Demizu Y. Recent advances in PROTAC technology toward new therapeutic modalities. Chem Biodivers 2022; 19(11): e202200828.
[http://dx.doi.org/10.1002/cbdv.202200828] [PMID: 36124821]
[41]
Xu H, Ohoka N, Yokoo H, et al. Development of agonist-based pROTACs targeting liver X receptor. Front Chem 2021; 9: 674967.
[http://dx.doi.org/10.3389/fchem.2021.674967] [PMID: 34124002]
[42]
Han X, Zhao L, Xiang W, et al. Discovery of highly potent and efficient PROTAC degraders of Androgen Receptor (AR) by employing weak binding affinity VHL E3 ligase ligands. J Med Chem 2019; 62(24): 11218-31.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01393] [PMID: 31804827]
[43]
Zhou C, Fan Z, Zhou Z, et al. Discovery of the first-in-class agonist-based SOS1 PROTACs effective in human cancer cells harboring various KRAS mutations. J Med Chem 2022; 65(5): 3923-42.
[http://dx.doi.org/10.1021/acs.jmedchem.1c01774] [PMID: 35230841]
[44]
Kim S, Chen J, Cheng T, et al. PubChem in 2021: New data content and improved web interfaces. Nucleic Acids Res 2021; 49(D1): D1388-95.
[http://dx.doi.org/10.1093/nar/gkaa971] [PMID: 33151290]
[45]
National Center for Biotechnology Information. 2022. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/bay-293 (Accessed on: December 21, 2022).
[46]
National Center for Biotechnology Information. 2022. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/bi-3406 (Accessed on: December 19, 2022).
[47]
National Center for Biotechnology Information. 2022. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/VHL-Ligand-8 (Accessed on: December 21, 2022).

Rights & Permissions Print Cite
Article Metrics
64
2
Wayfinder Image
World Suicide Prevention Day
© 2024 Bentham Science Publishers | Privacy Policy