Small molecule Son of Sevenless 1 (SOS1) inhibitors: a review of the patent literature

References

• McCormick F. K-Ras protein as a drug target. J Mol Med. 2016;94(3):253–258.
   PubMed Web of Science ®Google Scholar
• Cox AD, Der CJ. Ras history. Small GTPases. 2010;1(1):2–27.
   PubMedGoogle Scholar
• McCormick F. ras GTPase activating protein: signal transmitter and signal terminator. Cell. 1989;56(1):5–8.
   PubMed Web of Science ®Google Scholar
• Bourne HR, Sanders DA, McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature. 1990;348(6297):125–132.
   PubMed Web of Science ®Google Scholar
• Cherfils J, Zeghouf M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev. 2013;93(1):269–309.
   PubMed Web of Science ®Google Scholar
• Hall BE, Bar-Sagi D, Nassar N. The structural basis for the transition from Ras-GTP to Ras-GDP. Proc Natl Acad Sci. 2002;99(19):12138–12142.
   PubMed Web of Science ®Google Scholar
• Egan SE, Giddings BW, Brooks MW, et al. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature. 1993;363(6424):45–51.
   PubMed Web of Science ®Google Scholar
• Li N, Batzer A, Daly R, et al. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature. 1993;363(6424):85–88.
   PubMed Web of Science ®Google Scholar
• Chardin P, Camonis J, Gale N, et al. Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993;260(5112):1338–1343.
   PubMed Web of Science ®Google Scholar
• Aronheim A, Engelberg D, Li N, et al. Membrane targeting of the nucleotide exchange factor Sos is sufficient for activating the Ras signaling pathway. Cell. 1994;78(6):949–961.
   PubMed Web of Science ®Google Scholar
• Karlovich C, Bonfini L, McCollam L, et al. In vivo functional analysis of the Ras exchange factor son of sevenless. Science. 1995;268(5210):576–579.
   PubMed Web of Science ®Google Scholar
• Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, et al. The structural basis of the activation of Ras by Sos. Nature. 1998;394(6691):337–343.
   PubMed Web of Science ®Google Scholar
• Hall BE, Yang SS, Boriack-Sjodin PA, et al. Structure-based mutagenesis reveals distinct functions for Ras switch 1 and switch 2 in Sos-catalyzed Guanine nucleotide exchange. J Biol Chem. 2001;276(29):27629–27637.
   PubMed Web of Science ®Google Scholar
• Boykevisch S, Zhao C, Sondermann H, et al. Regulation of Ras signaling dynamics by Sos-Mediated positive feedback. Curr Biol. 2006;16(21):2173–2179.
   PubMed Web of Science ®Google Scholar
• Gureasko J, Galush WJ, Boykevisch S, et al. Membrane-dependent signal integration by the Ras activator Son of sevenless. Nat Struct Mol Biol. 2008;15(5):452–461.
   PubMed Web of Science ®Google Scholar
• Rojas JM, Oliva JL, Santos E. Mammalian son of sevenless Guanine nucleotide exchange factors: old concepts and new perspectives. Genes Cancer. 2011;2(3):298–305.
   PubMedGoogle Scholar
• Iversen L, Tu H-L, Lin W-C, et al. Ras activation by SOS: allosteric regulation by altered fluctuation dynamics. Science. 2014;345(6192):50–54.
   PubMed Web of Science ®Google Scholar
• Christensen SM, Tu H-L, Jun JE, et al. One-way membrane trafficking of SOS in receptor-triggered Ras activation. Nat Struct Mol Biol. 2016;23(9):838–846.
   PubMed Web of Science ®Google Scholar
• Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 20072007/06/01/;129(5):865–877.
   PubMed Web of Science ®Google Scholar
• Qi M, Elion EA. MAP kinase pathways. J Cell Sci. 2005;118(16):3569–3572.
   PubMed Web of Science ®Google Scholar
• Krygowska AA, Castellano E. PI3K: a crucial piece in the RAS signaling puzzle. Cold Spring Harb Perspect Med. 2018;8(6):a031666.
   PubMed Web of Science ®Google Scholar
• Der CJ, Krontiris TG, Cooper GM. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc Natl Acad Sci. 1982;79(11):3637–3640.
   PubMed Web of Science ®Google Scholar
• Santos E, Tronick SR, Aaronson SA, et al. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature. 1982;298(5872):343–347.
   PubMed Web of Science ®Google Scholar
• Parada LF, Tabin CJ, Shih C, et al. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature. 1982;297(5866):474–478.
   PubMed Web of Science ®Google Scholar
• Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11(11):761–774.
   PubMed Web of Science ®Google Scholar
• Prior IA, Lewis PD, Mattos C. Survey of Ras Mutations in Cancer. Cancer Res. 2012;72(10):2457–2467.
   PubMed Web of Science ®Google Scholar
• Bryant KL, Mancias JD, Kimmelman AC, et al. KRAS: feeding pancreatic cancer proliferation. Trends Biochem Sci. 2014;39(2):91–100.
   PubMed Web of Science ®Google Scholar
• Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129(7):1287–1292.
   PubMed Web of Science ®Google Scholar
• Simanshu DK, Nissley DV, McCormick F. Their regulators in human disease. Cell. 2017;170(1):17–33.
   PubMed Web of Science ®Google Scholar
• Bernards A, Settleman J. GAP control: regulating the regulators of small GTPases. Trends Cell Biol. 2004;14(7):377–385.
   PubMed Web of Science ®Google Scholar
• Hunter JC, Manandhar A, Carrasco MA, et al. Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. Mol Cancer Res. 2015;13(9):1325–1335.
   PubMed Web of Science ®Google Scholar
• Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11–22.
   PubMed Web of Science ®Google Scholar
• Ryan MB, Corcoran RB. Therapeutic strategies to target RAS-mutant cancers. Nat Rev Clin Oncol. 2018;15(11):709–720.
   PubMed Web of Science ®Google Scholar
• Cox AD, Fesik SW, Kimmelman AC, et al. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828–851.
   PubMed Web of Science ®Google Scholar
• Chen H, Smaill JB, Liu T, et al. Small-Molecule inhibitors directly targeting KRAS as anticancer therapeutics. J Med Chem. 2020;63(23):14404–14424.
   PubMed Web of Science ®Google Scholar
• Ostrem JM, Peters U, Sos ML, et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548–551.
   PubMed Web of Science ®Google Scholar
• Patricelli MP, Janes MR, Li L-S, et al. Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov. 2016;6(3):316–329.
   PubMed Web of Science ®Google Scholar
• Janes MR, Zhang J, Li L-S, et al. Targeting KRAS mutant cancers with a covalent G12C-Specific inhibitor. Cell. 2018;172(3):578–589.
   PubMed Web of Science ®Google Scholar
• Fell JB, Fischer JP, Baer BR, et al. Discovery of tetrahydropyridopyrimidines as irreversible covalent inhibitors of KRAS-G12C with in vivo activity. ACS Med Chem Lett. 2018;9(12):1230–1234.
   PubMed Web of Science ®Google Scholar
• Shin Y, Jeong JW, Wurz RP, et al. Discovery of N-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as covalent inhibitors of KRASG12C. ACS Med Chem Lett. 2019;10(9):1302–1308.
   PubMed Web of Science ®Google Scholar
• Kettle JG, Bagal SK, Bickerton S, et al. Structure-Based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant GTPase KRASG12C. J Med Chem. 2020;63(9):4468–4483.
   PubMed Web of Science ®Google Scholar
• Fell JB, Fischer JP, Baer BR, et al. Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer. J Med Chem. 2020;63(13):6679–6693.
   PubMed Web of Science ®Google Scholar
• Nagasaka M, Li Y, Sukari A, et al. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev. 2020;84:101974.
   PubMed Web of Science ®Google Scholar
• Nichols RJ, Cregg J, Schulze CJ, et al. A next generation tri-complex KRASG12C(ON) inhibitor directly targets the active, GTP-bound state of mutant RAS and may overcome resistance to KRASG12C(OFF) inhibition. Poster session presented at: 112th Annual Meeting of the American Association for Cancer Research; April 10-15; Philadelphia, PA 2021.
   Google Scholar
• Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575(7781):217–223.
   PubMed Web of Science ®Google Scholar
• Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383(13):1207–1217.
   PubMed Web of Science ®Google Scholar
• Lanman BA, Allen JR, Allen JG, et al. Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors. J Med Chem. 2020;63(1):52–65.
   PubMed Web of Science ®Google Scholar
• Wildman SA, Crippen GM. Prediction of physicochemical parameters by atomic contributions. J Chem Inf Comput Sci. 1999;39(5):868–873.
   Google Scholar
• RDKit: Open-source cheminformatics. Available from: https://www.rdkit.org
   Google Scholar
• Wortmann L, Sautier B, Eis K, et al., inventors; Bayer Pharma Aktiengesellschaft, assignee. Preparation of 2-methylquinazolines for treating hyperproliferative disorders patent WO2018172250. 2018.
   Google Scholar
• Wortmann L, Sautier B, Eis K, et al., inventors; Bayer Pharma Aktiengesellschaft assignee. Preparation of 2-methyl-aza-quinazolines for inhibiting binding of hSOS1 to hKRAS patent WO2019201848. 2019.
   Google Scholar
• Wortmann L, Graham K, Bader B, et al., inventors; Bayer Aktiengesellschaft, assignee. 2-METHYL-AZA-QUINAZOLINES patent WO2021074227. 2021.
   Google Scholar
• 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. 116(7): 2551–2560. 2019. .
   PubMed Web of Science ®Google Scholar
• Gmachl M, Sanderson M, Kessler D, et al., inventors; Boehringer Ingelheim International GmbH, assignee. Preparation of benzylamino substituted quinazolines as SOS1 inhibitors for the treatment of cancer patent WO2018115380. 2018.
   Google Scholar
• Ramharter J, Kofink C, Stadtmueller H, et al., inventors; Boehringer Ingelheim International GmbH, assignee. Preparation of the novel benzylamino substituted pyridopyrimidinones and derivatives as SOS1 inhibitors patent WO2019122129. 2019.
   Google Scholar
• Ramharter J, Kessler D, Ettmayer P, et al. One atom makes all the difference: getting a foot in the door between SOS1 and KRAS. J Med Chem. 2021;64(10):6569–6580.
   PubMed Web of Science ®Google Scholar
• Janes MR, Patricelli MP, Li L, et al., inventors; araxes pharma LLC, assignee. Combination therapies for treatment of cancer patent WO2016044772. 2016.
   Google Scholar
• 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. 11(1): 142–157. 2021. .
   PubMed Web of Science ®Google Scholar
• Kessler D, Gerlach D, Kraut N, et al. Targeting Son of Sevenless 1: the pacemaker of KRAS. Curr Opin Chem Biol. 2021;62:109–118.
   PubMed Web of Science ®Google Scholar
• Boehringer Ingelheim. A study to test different doses of BI 1701963 alone and combined with trametinib in patients with different types of advanced cancer (Solid Tumours With KRAS Mutation) Bethesda (MD): U.S. National Library of Medicine; 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT04111458 ClinicalTrials.gov Identifier: NCT04111458
   Google Scholar
• Boehringer Ingelheim. A study to test different doses of bi 1701963 in combination with irinotecan in people with advanced bowel cancer with Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) mutation. Bethesda (MD): U.S. National Library of Medicine; 2020. Available from: https://clinicaltrials.gov/ct2/show/NCT04627142 ClinicalTrials.gov Identifier: NCT04627142
   Google Scholar
• Boehringer Ingelheim. A study to find a safe and effective dose of BI 1701963 alone and in combination with BI 3011441 in patients with advanced cancer and a certain mutation (KRAS) bethesda (MD): U.S. national library of medicine; 2021. Available from: https://clinicaltrials.gov/ct2/show/NCT04835714 ClinicalTrials.gov Identifier: NCT04835714
   Google Scholar
• Buckl A, Cregg JJ, Aay N, et al., inventors; Revolution Medicines, Inc., assignee. Preparation of bicyclic heteroaryl compounds and uses thereof. patent WO2020180768. 2020.
   Google Scholar
• Cregg JJ, Buckl A, Aay N, et al., inventors; Revolution Medicines Inc., assignee. Bicyclic heterocyclyl compounds and uses thereof. Patent WO2020180770. 2020
   Google Scholar
• Gill AL, Buckl A, Koltun ES, et al., inventors; Revolution Medicines, inc., assignee. Bicyclic Heteroaryl Compounds and Uses Thereof patent WO2021092115. 2021.
   Google Scholar
• Waterson AG, Abbott JR, Kennedy JP, et al., inventors; Vanderbilt University, assignee. Quinazoline compounds as modulators of Ras signaling and their preparation patent WO2018212774. 2018.
   Google Scholar
• Fesik S, Waterson A, Burns M, et al., inventors; Vanderbilt University, assignee. Preparation of substituted benzimidazoles as modulators of Ras signaling patent US10501421. 2019.
   Google Scholar
• 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. 2014;111(9):3401–3406.
   PubMed Web of Science ®Google Scholar
• Abbott JR, Hodges TR, Daniels RN, et al. Discovery of aminopiperidine indoles that activate the guanine nucleotide exchange factor SOS1 and modulate RAS signaling. J Med Chem. 2018;61(14):6002–6017.
   PubMed Web of Science ®Google Scholar
• Abbott JR, Patel PA, Howes JE, et al., Discovery of quinazolines that activate SOS1-Mediated nucleotide exchange on RAS. ACS Med Chem Lett. 9(9): 941–946. 2018. .
   PubMed Web of Science ®Google Scholar
• 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. 61(19): 8875–8894. 2018. .
   PubMed Web of Science ®Google Scholar
• Sun Q, Burke JP, Phan J, et al. Discovery of small molecules that bind to K-Ras and inhibit Sos-Mediated activation. Angewandte Chemie. 2012;51(25):6140–6143.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Martin SJ. Oncogene-induced autophagy and the Goldilocks principle. Autophagy. 2011;7(8):922–923.
   PubMed Web of Science ®Google Scholar
• Chi S, Kitanaka C, Noguchi K, et al. Oncogenic Ras triggers cell suicide through the activation of a caspase-independent cell death program in human cancer cells. Oncogene. 1999;18(13):2281–2290.
   PubMed Web of Science ®Google Scholar
• Overmeyer JH, Kaul A, Johnson EE, et al. Active Ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis. Mol Cancer Res. 2008;6(6):965–977.
   PubMed Web of Science ®Google Scholar
• Lv C, Hong Y, Miao L, et al. Wentilactone A as a novel potential antitumor agent induces apoptosis and G2/M arrest of human lung carcinoma cells, and is mediated by HRas-GTP accumulation to excessively activate the Ras/Raf/ERK/p53-p21 pathway. Cell Death Dis. 2013;4(12):e952–e952.
   PubMedGoogle Scholar
• Langlois WJ, Sasaoka T, Saltiel AR, et al. Negative feedback regulation and desensitization of insulin- and epidermal growth factor-stimulated p21ras activation. J Biol Chem. 1995;270(43):25320–25323.
   PubMed Web of Science ®Google Scholar
• Porfiri E, McCormick F. Regulation of epidermal growth factor receptor signaling by phosphorylation of the ras exchange factor hSOS1. J Biol Chem. 1996;271(10):5871–5877.
   PubMed Web of Science ®Google Scholar
• Corbalan-Garcia S, Yang SS, Degenhardt KR, et al. Identification of the mitogen-activated protein kinase phosphorylation sites on human Sos1 that regulate interaction with Grb2. Mol Cell Biol. 1996;16(10):5674–5682.
   PubMed Web of Science ®Google Scholar
• Kamioka Y, Yasuda S, Fujita Y, et al. Multiple decisive phosphorylation sites for the negative feedback regulation of SOS1 via ERK. J Biol Chem. 2010;285(43):33540–33548.
   PubMed Web of Science ®Google Scholar
• Lake D, Corrêa SAL, Müller J. Negative feedback regulation of the ERK1/2 MAPK pathway. Cell Mol Life Sci. 2016;73(23):4397–4413.
   PubMed Web of Science ®Google Scholar
• Howes JE, Akan DT, Burns MC, et al. 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):1051–1060.
   PubMed Web of Science ®Google Scholar
• Sheffels E, Sealover NE, Wang C, et al. Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation. Sci Signal. 2018;11(546):eaar8371.
   PubMed Web of Science ®Google Scholar
• Sheffels E, Sealover NE, Theard PL, et al. Anchorage-independent growth conditions reveal a differential SOS2 dependence for transformation and survival in RAS-mutant cancer cells. Small GTPases. 2019;12(1):67–78.
   PubMedGoogle Scholar
• Sheffels E, Kortum RL. Breaking oncogene addiction: getting RTK/RAS-Mutated cancers off the SOS. J Med Chem. 2021;64(10):6566–6568.
   PubMed Web of Science ®Google Scholar
• Baltanás FC, Pérez-Andrés M, Ginel-Picardo A, et al. Functional redundancy of Sos1 and Sos2 for lymphopoiesis and organismal homeostasis and survival. Mol Cell Biol. 2013;33(22):4562–4578.
   PubMed Web of Science ®Google Scholar
• Baltanás FC, García-Navas R, Santos E. SOS2 comes to the fore: differential functionalities in physiology and pathology. Int J Mol Sci. 2021;22(12):6613.
   PubMed Web of Science ®Google Scholar