Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders

Lingying Leng; Wenbin Tu; Lin Yang; Liyue Huang; Mi Wang; Jennifer L Meagher; Krishnapriya Chinnaswamy; Srinivasa Rao Allu; Rohan Kalyan Rej; Jelena Tošović; Lalgudi Harikrishnan; Zhenwu Li; Zhihua Sui; Jeanne A Stuckey; Shaomeng Wang

doi:10.1021/acs.jmedchem.4c01903

Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders

J Med Chem. 2025 Jan 2. doi: 10.1021/acs.jmedchem.4c01903. Online ahead of print.

Authors

Lingying Leng¹, Wenbin Tu^{1

2}, Lin Yang¹, Liyue Huang¹, Mi Wang¹, Jennifer L Meagher³, Krishnapriya Chinnaswamy³, Srinivasa Rao Allu¹, Rohan Kalyan Rej¹, Jelena Tošović¹, Lalgudi Harikrishnan⁴, Zhenwu Li⁴, Zhihua Sui⁴, Jeanne A Stuckey^{3

5}, Shaomeng Wang^{1

2

6

5}

Affiliations

¹ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109, United States.
² Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
³ Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, United States.
⁴ SK Life Science Laboratories, 2500 Renaissance Blvd, King of Prussia, Pennsylvania 19406, United States.
⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, United States.
⁶ Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109, United States.

PMID: 39745064
DOI: 10.1021/acs.jmedchem.4c01903

Abstract

In the SWI/SNF chromatin-remodeling complex, the mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting SMARCA2 for degradation is a promising and new therapeutic strategy for human cancers harboring inactivated mutated SMARCA4. In this study, we report the design, synthesis, and biological evaluation of novel SMARCA2/4 ligands and our subsequent design of PROTAC degraders using high-affinity SMARCA ligands and VHL-1 ligands. Our efforts led to the discovery of high-affinity SMARCA2/4 bromodomain ligands and the development of a potent and selective SMARCA2 degrader and a highly potent SMARCA2/4 and PBRM1 degrader.