Author: Xia, Yan ; O'Neill, Raymond ; Hrizat, Alaa S ; Eberle-Singh, Jaime ; McCue, Peter A ; Lin, Ruihe ; Yang, Haifeng ; Testa, Joseph R ; Uzzo, Robert ; Li, Li

BACKGROUNDPatients with clear cell renal cell carcinoma (ccRCC) metastases face poor prognoses, even with adjuvant therapies. Tumor-infiltrating T-cells and macrophages are critical in targeting tumor cells within the renal microenvironment. Beyond VHL mutations, loss-of-function mutations in SWI/SNF complex genes, including PBRM1, BAP1, ARID1A, SETD2, SMARCA4 (BRG1), and SMARCA2 (BRM), have been implicated in ccRCC progression.DESIGNA tissue microarray of 160 ccRCC cases was analyzed via immunohistochemistry (IHC) for SWI/SNF protein expression and CD4 + /CD8 + T-cell infiltration. Clinical and pathologic features were obtained through electronic medical records. Statistical analyses included one-way ANOVA, two-way ANOVA, Pearson's chi-square and t-tests.RESULTSLoss of SWI/SNF protein expression was observed in PBRM1 (31 %), ARID1A (51 %), SETD2 (14 %), BRG1 (15 %), BRM (38 %), and BAP1 (40 %). T-cell counts varied significantly with stage: CD4 + counts peaked at Stage 3, while CD8 + counts increased through Stage 4 (p < 0.001). Loss of PBRM1 was more frequent in advanced stages (29.4 %, p < 0.001), while BRM and BRG1 losses were more common in earlier stages (p < 0.001, p = 0.006). ARID1A and BRM losses correlated with reduced CD8 + counts (p = 0.016, p = 0.032) and stage-specific CD4 + variations (p < 0.001, p = 0.042).CONCLUSIONLoss of PBRM1, SMARCA2/BRM, and SMARCA4/BRG1 expression is significantly associated with ccRCC progression, with PBRM1 loss prevalent in advanced stages and SMARCA2/BRM and SMARCA4/BRG1 in earlier stages. ARID1A and SMARCA2/BRM losses correlate with reduced CD8 + counts and stage-specific CD4 + infiltration, highlighting their potential as biomarkers for disease progression and immunotherapeutic response.

09 Apr 2024·Proceedings of the National Academy of Sciences

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer

Article

Author: Abbineni, Chandrasekhar ; Zheng, Yang ; Dukare, Sandeep ; Zeng, Victoria Z ; Cao, Xuhong ; Young, Eleanor ; Parolia, Abhijit ; Lyssiotis, Costas A ; Vaishampayan, Ulka ; Cheng, Caleb ; Wang, Rui ; Chang, Yu ; He, Tongchen ; Su, Fengyun ; Chinnaiyan, Arul M ; Miner, Stephanie J ; Wisniewski, Jasmine P ; Hou, Siyu ; Qiao, Yuanyuan ; Cho, Hanbyul ; Kuila, Bilash ; Mahapatra, Somnath ; D S, Samiulla ; Kim, NamHoon ; Jackson, Bailey ; Mukherjee, Subhendu ; Mannan, Rahul ; Xiao, Lanbo ; Aithal, Kiran B

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

28 Sep 2023·Journal of Medicinal ChemistryQ1 · MEDICINE

GNE-235: A Lead Compound Selective for the Second Bromodomain of PBRM1

Q1 · MEDICINE

Article

Author: Flynn, Megan ; Cochran, Andrea G

Bromodomains are acetyl-lysine binding modules that are found in different classes of chromatin-interacting proteins. Among these are large chromatin remodeling complexes such as BAF and PBAF (variants of human SWI/SNF). Previous work has identified chemical probes targeting a subset of the bromodomains present in the BAF and PBAF complexes. Selective inhibitors of the individual bromodomains have proven challenging to discover, as the domains are highly similar. Here, elaboration of an aminopyridazine scaffold used previously to develop probes for the bromodomains of SMARCA2, SMARCA4, and the fifth bromodomain of PBRM1 yielded compounds with both potency and unusual selectivity for the second bromodomain of PBRM1. One of these, GNE-235, and its enantiomer control GNE-234 are suggested for initial cellular investigations of the function of the second bromodomain of PBRM1.

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