2. Academic Validation
  3. Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer

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

  • bioRxiv. 2024 Mar 2:2024.02.29.582768. doi: 10.1101/2024.02.29.582768.
Tongchen He 1 2 3 4,  Caleb Cheng 1 5 6 4,  Yuanyuan Qiao 1 2 7,  Hanbyul Cho 1 2,  Eleanor Young 1 2,  Rahul Mannan 1 2,  Somnath Mahapatra 1 2,  Stephanie J Miner 1 2,  Yang Zheng 1 2,  NamHoon Kim 1,  Victoria Z Zeng 1,  Jasmine P Wisniewski 1,  Siyu Hou 8,  Bailey Jackson 1,  Xuhong Cao 1 2 9,  Fengyun Su 1 2,  Rui Wang 1 2,  Yu Chang 1 2,  Bilash Kuila 10,  Subhendu Mukherjee 10,  Sandeep Dukare 10,  Kiran B Aithal 10,  Samiulla D S 10,  Chandrasekhar Abbineni 10,  Costas A Lyssiotis 7 11 12,  Abhijit Parolia 1 2 7,  Lanbo Xiao 1 2 7,  Arul M Chinnaiyan 1 2 7 9 13
Affiliations

Affiliations

  • 1 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 2 Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 3 Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
  • 4 These authors contributed equally.
  • 5 Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA.
  • 6 Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, MI, USA.
  • 7 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 8 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
  • 9 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
  • 10 Aurigene Oncology Limited, Bangalore, India.
  • 11 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 12 Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
  • 13 Department of Urology, University of Michigan, Ann Arbor, MI, USA.
PMID: 38464081 DOI: 10.1101/2024.02.29.582768
Abstract

Mammalian switch/sucrose non-fermentable (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, a first-in-class, 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 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 (BRD4) 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.

Keywords

ABCB1; SMARCA2 and SMARCA4; mSWI/SNF; proteolysis targeting chimera (PROTAC).

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