Synthetic lethality: targeting the SMARCA2 bromodomain for degradation in SMARCA4-deficient tumors – a review of patent literature from 2019–June 2023

References

• Wilson BG, Roberts CWM. SWI/SNF nucleosome remodelers and cancer. Nat Rev Cancer. 2011;11(7):481–492. doi: 10.1038/nrc3068
   PubMed Web of Science ®Google Scholar
• Kadoch C, Hargreaves DC, Hodges C, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45(6):592–601. doi: 10.1038/ng.2628
   PubMed Web of Science ®Google Scholar
• Centore RC, Sandoval GJ, Soares LMM, et al. Mammalian SWI/SNF chromatin remodeling complexes: emerging mechanisms and therapeutic strategies. Trends Genet. 2020;36(12):936–950. doi: 10.1016/j.tig.2020.07.011
   PubMed Web of Science ®Google Scholar
• Medina PP, Carretero J, Fraga MF, et al. Genetic and epigenetic screening for gene alterations of the chromatin-remodeling factor, SMARCA4/BRG1, in lung tumors. Genes Chromosomes Cancer. 2004;41(2):170–177. doi: 10.1002/gcc.20068
   PubMed Web of Science ®Google Scholar
• Hoffman GR, Rahal R, Buxton F, et al. Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc Natl Acad Sci USA. 2014;111(8):3128–3133. doi: 10.1073/pnas.1316793111
   PubMed Web of Science ®Google Scholar
• Oike T, Ogiwara H, Tominaga Y, et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res. 2013;73(17):5508–5518. doi: 10.1158/0008-5472.CAN-12-4593
   PubMed Web of Science ®Google Scholar
• Helming KC, Wang X, Roberts CWM. Vulnerabilities of mutant SWI/SNF complexes in cancer. Cancer Cell. 2014;26(3):309–317. doi: 10.1016/j.ccr.2014.07.018
   PubMed Web of Science ®Google Scholar
• Jain AK, Barton MC. Bromodomain histone readers and cancer. J Mol Biol. 2017;429(13):2003–2010. doi: 10.1016/j.jmb.2016.11.020
   PubMed Web of Science ®Google Scholar
• Gerstenberger BS, Trzupek JD, Tallant C, et al. Identification of a chemical probe for family VIII bromodomains through optimization of a fragment hit. J Med Chem. 2016;59(10):4800–4811. doi: 10.1021/acs.jmedchem.6b00012
   PubMed Web of Science ®Google Scholar
• Vangamudi B, Paul TA, Shah PK, et al. The SMARCA2/4 ATPase domain surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant cancers: insights from cDNA rescue and PFI-3 inhibitor studies. Cancer Res. 2015;75(18):3865–3878. doi: 10.1158/0008-5472.CAN-14-3798
   PubMed Web of Science ®Google Scholar
• Burslem GM, Crews CM. Small-molecule modulation of protein homeostasis. Chem Rev (Washington, DC, U S). 2017;117(17):11269–11301. doi: 10.1021/acs.chemrev.7b00077
   PubMed Web of Science ®Google Scholar
• Toure M, Crews C-M. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem Int Ed. 2016;55(6):1966–1973. doi: 10.1002/anie.201507978
   PubMed Web of Science ®Google Scholar
• Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001;98(15):8554–8559. doi: 10.1073/pnas.141230798
   PubMed Web of Science ®Google Scholar
• Taylor AM, Bailey C, Belmont LD, et al. GNE-064: a potent, selective, and orally bioavailable chemical probe for the Bromodomains of SMARCA2 and SMARCA4 and the fifth bromodomain of PBRM1. J Med Chem. 2022;65(16):11177–11186. doi: 10.1021/acs.jmedchem.2c00662
   PubMed Web of Science ®Google Scholar
• Sutherell CL, Tallant C, Monteiro OP, et al. Identification and development of 2,3-Dihydropyrrolo[1,2-a]quinazolin-5(1H)-one inhibitors targeting bromodomains within the Switch/Sucrose nonfermenting complex. J Med Chem. 2016;59(10):5095–5101. doi: 10.1021/acs.jmedchem.5b01997
   PubMed Web of Science ®Google Scholar
• Guenette RG, Yang SW, Min J, et al. Target and tissue selectivity of PROTAC degraders. Chem Soc Rev. 2022;51(14):5740–5756. doi: 10.1039/D2CS00200K
   PubMed Web of Science ®Google Scholar
• Gopalsamy A. Selectivity through targeted protein degradation (TPD). J Med Chem. 2022;65(12):8113–8126. doi: 10.1021/acs.jmedchem.2c00397
   PubMed Web of Science ®Google Scholar
• Banerjee A, Cee VJ, Chen N, et al., inventors; Amgen Inc. assignee. Preparation of piperazine derivatives and related heterocycles as SMARCA2-VHL degraders for the treatment of SMARCA2-mpediated diseases patent WO2021142247. 2021.
   Google Scholar
• Crew AP, Wang J, Berlin M, et al., inventors; Arvinas Operations, Inc. assignee. Preparation of bifunctional PROTAC compounds and methods for degradation of targeted BRM proteins patent US20190300521. 2019.
   Google Scholar
• Crew AP, Wang J, Berlin M, et al., inventors; Arvinas Operations, Inc. Genentech, Inc. assignee. Preparation of pyridazinamine derivatives as modulators of SMARCA2 and BRM target proteins and associated methods of use patent WO2021067606. 2021.
   Google Scholar
• Cantley J, Ye X, Rousseau E, et al. Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers. Nat Commun. 2022;13(1):6814. doi: 10.1038/s41467-022-34562-5
   PubMed Web of Science ®Google Scholar
• Berlin M, Broccatelli F, Chen H, et al., inventors; Arvinas Operations, Inc. Genentech, Inc. assignee. Preparation of bifunctional compounds as modulators of SMARCA2 and BRM target proteins and associated methods of use patent WO2023097031. 2023.
   Google Scholar
• Berlin M, Chen H, Dragovich PS, et al., inventors; Arvinas Operations, Inc. Genentech, Inc. assignee. Preparation of bifunctional compounds as modulators of SMARCA2 and BRM target proteins and associated methods of use patent WO2023096987. 2023.
   Google Scholar
• Sasmal S, Samajdar S, Mukherjee S, et al., inventors; Aurigene Discovery Technologies Limited, assignee. Preparation of pyridazine derivatives as SMARCA2/4 degraders patent WO2019207538. 2019.
   Google Scholar
• Abbineni C, Samajdar S, Kuila B, et al., inventors; Aurigene Discovery Technologies Limited, assignee. Preparation of 6-substituted pyridazine compounds containing prolyl peptides as SMARCA2 and/or SMARCA4 degraders patent WO2022029617. 2022.
   Google Scholar
• Ciulli A, Dank C, Diers E, et al., inventors; Boehringer Ingelheim International GmbH, assignee. Proteolysis targeting chimera (PROTACs) as degraders of SMARCA2 and/or SMARCA4 patent WO2020078933. 2020.
   Google Scholar
• Ciulli A, Diers E, Farnaby W, et al., inventors; Boehringer Ingelheim International GmbH, assignee. Preparation of novel imidazoquinazolines and proteolysis targeting chimera (PROTACs) comprising them as degraders of SMARCA patent WO2023052363. 2023.
   Google Scholar
• Kofink C, Trainor N, Mair B, et al. A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo. Nat Commun. 2022(13):5969. doi: 10.1038/s41467-022-33430-6
   PubMed Web of Science ®Google Scholar
• Duplessis M, Gaufreteau D, Hutter R, et al., inventors; F. Hoffmann-La Roche AG, Hoffmann-La Roche Inc. C4 Therapeutics, Inc. assignee. 3-Aminopyridazine bifunctional compounds as SMARCA2 protein inhibitors and their preparation, pharmaceutical compositions and use in the treatment of the treatment of cancer patent WO2021083949. 2021.
   Google Scholar
• Riching KM, Mahan SD, Urh M, et al. High-throughput cellular profiling of targeted protein degradation compounds using HiBiT CRISPR cell lines. J Visualized Exp. 2020;165(165):e61693. doi: 10.3791/61787
   Google Scholar
• Gaufreteau D, Hutter R, Jovcheva E, et al., inventors; F. Hoffmann-La Roche AG C4 Therapeutics, Inc. Hoffmann-La Roche Inc. assignee. 3-Aminopyridazine bifunctional compounds as SMARCA2 protein inhibitors and their preparation, pharmaceutical compositions and use in the treatment of the treatment of cancer patent WO2021086785. 2021.
   Google Scholar
• Netherton M, Brucelle F, inventors; Foghorn Therapeutics Inc. assignee. Preparation of substituted hydroxyphenylpyridazinamines for treating BAF complex-related disorders patent WO2021207291. 2021.
   Google Scholar
• Netherton M, Brucelle F, Deng J, et al., inventors; Foghorn Therapeutics Inc. assignee. Preparation of arylpyridazinamine compounds and uses thereof patent WO2022109396. 2022.
   Google Scholar
• Netherton M, Brucelle F, Deng J, et al., inventors; Foghorn Therapeutics Inc. assignee. Preparation of arylpyrrolopyridazinamine compounds and related derivatives useful for modulating BRG1- or BRM-associated factors (BAF) complexes and for treating cancer and viral infection patent WO2022109426. 2022.
   Google Scholar
• Netherton M, Brucelle F, Deng J, et al., inventors; Foghorn Therapeutics Inc. assignee. Preparation of arylthienopyridazines, arylbenzothienopyridazines and related compounds containing a dipeptidyl degradation moiety useful for modulating BRG1- or BRM-associated factors (BAF) complexes and for treating cancer and viral infection patent WO2022240825. 2022.
   Google Scholar
• Gu P, Zeng F, Yu Z, et al., inventors; Jiangsu Simcere Pharmaceutical Co. Ltd. assignee. BRM selective degradation agent compound and use thereof patent WO2023093728. 2023.
   Google Scholar
• Ji N, Kluge AF, Weiss MM, et al., inventors; Kymera Therapeutics, Inc. assignee. Preparation of novel bifunctional compounds as protein degraders and uses thereof patent WO2020010227. 2020.
   Google Scholar
• Ji N, Zhang Y, Sintchak MD, et al., inventors; Kymera Therapeutics, Inc. assignee. Preparation of heterocyclic compounds as SMARCA degraders and uses thereof patent WO2020251972. 2020.
   Google Scholar
• Zhang Y, Fleming PR, Zhu X, inventors; Kymera Therapeutics, Inc. assignee. Preparation of bifunctional heterocyclic SMARCA degraders patent WO2021133920. 2021.
   Google Scholar
• Zhang Y, Fleming PR, Zhu X, et al., inventors; Kymera Therapeutics, Inc. assignee. Heterocycles as SMARCA degraders and preparation and uses thereof patent WO2023278402. 2023.
   Google Scholar
• Zhang Y, Zheng X, Zhu X, inventors; Kymera Therapeutics, Inc. assignee. Preparation of bifunctional compounds as SMARCA degraders patent WO2022125804. 2022.
   Google Scholar
• Combs AP, Lin H, Pitis P, et al., inventors; Prelude Therapeutics, Incorporated, assignee. Brm targeting compounds and associated methods of use patent WO2021252666. 2021.
   Google Scholar
• Lu L, Combs AP, Basch CH, et al., inventors; Prelude Therapeutics Incorporated, assignee. BRM targeting compounds and associated methods of use patent WO2022099117. 2022.
   Google Scholar
• Lu L, Combs AP, inventors; Prelude Therapeutics, Incorporated, assignee. Preparation of pyridazine derivatives as BRM targeting compounds and E3 ubiquitin ligase binding agents for the treatment of cancers patent WO2023287787. 2023.
   Google Scholar
• Prelude Therapeutics. PRT3789 Monotherapy and in Combo w/Docetaxel in Participants w/Advanced or Metastatic Solid Tumors w/SMARCA4 Mutation. Bethesda (MD): U.S. National Library of Medicine; 2023. Available from: https://www.clinicaltrials.gov/study/NCT05639751
   Google Scholar
• Hulse ME, Margot B, Jessica V, Komali P, Philip L, Liang V, Kris C, Andrew I, Koichi S. Peggy, editor Combination therapy with selective SMARCA2 (BRM) degraders for treatment of SMARCA4 (BRG1)-deficient cancers. Orlando (FL). American Association for Cancer Research; 2023.
   Google Scholar
• Bultman S, Gebuhr T, Yee D, et al. A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol Cell. 2000;6(6):1287–1295. doi: 10.1016/S1097-2765(00)00127-1
   PubMed Web of Science ®Google Scholar
• Berlin M, Cantley J, Bookbinder M, et al. Protacs targeting BRM (SMARCA2) afford selective in vivo degradation over BRG1 (SMARCA4) and are active in BRG1 mutant xenograft tumor models. J Med Chem. 2024;67(2):1262–1313. doi: 10.1021/acs.jmedchem.3c01781
   PubMed Web of Science ®Google Scholar
• Foghorn Provides Pipeline Update on FHD-909 BRM Selective Inhibitor [Internet] 2024 Feb 8. Available from: https://ir.foghorntx.com/news-releases/news-release-details/foghorn-provides-pipeline-update-fhd-909-brm-selective-inhibitor
   Google Scholar
• Reichl KD, Lee EC, Gopalsamy A. Synthetic lethality: targeting SMARCA2 ATPase in SMARCA4-deficient tumors – a review of patent literature from 2019–30 June 2023. Expert Opinion on Therapeutic Patents. 2024;34(3):159–169. doi: 10.1080/13543776.2024.2338111
   PubMedGoogle Scholar