Abstract B113: Discovery of PRT3789, a first-in-class potent and selective SMARCA2 degrader in clinical trials for the treatment of patients with SMARCA4 mutated cancers

作者：Koichi Ito, Michael W Hulse, Anjana Agarwal, Jack Carter, Monisha Sivakumar, Komali Vykuntam, Min Wang, Miles Cowart, Joy M. Cote, William Gowen-MacDonald, Brian Vidal Torres, Justin J. Kurian, Neha Bhagwat, Norman Fultang, Alexander Grego, Andrew W. Moore, Ashley Schwab, Jessica Burtell, Olusola Peace Osinubi, Jacob Spruance, Liang Lü, Philip M. Pitis, Corey Hannah Basch, Klare Bersch, Chaofeng Dai, Raul Leal, Artem Shvartsbart, Ganfeng Cao, Bo Shen, Patrick Yung Wen, Joseph D. Rager, Ross Kuskovsky, Bob Landman, Tom Emm, Stefan U. Ruepp, Chunhua Qin, Gina Paris, Jennifer Xavier, Rachel A. Chiaverelli, Sang‐Hyun Lee, Sandy Geeganage, Hong Lin, Diane Heiser, Bruce Ruggeri, Naveen Babbar, Andrew P. Combs, Peggy Scherle · 发表于：Molecular Cancer Therapeutics · 年份：2023 · DOI：10.1158/1535-7163.targ-23-b113 · 被引用次数：4 · 研究领域：Chromatin Remodeling and Cancer、Peptidase Inhibition and Analysis、Cancer Mechanisms and Therapy

Abstract SWI/SNF complexes play an important role in controlling gene expression by remodeling chromatin. SMARCA2 (BRM) and SMARCA4 (BRG1) are the core catalytic subunits of the SWI/SNF complexes. SMARCA4 expression is lost in some cancers due to its gene mutations, and SMARCA4-deficient cancer cells are highly dependent on its paralog gene SMARCA2 for their survival. SMARCA4 mutation is associated with worse patient prognosis and reduced responsiveness to inhibitors of KRAS G12C or immune checkpoint, compared to patients with SMARCA4 WT cancers. Furthermore, SMARCA4 mutation is often mutually exclusive with other targetable oncogenic alterations such as EGFR, ALK, MET, RET and ROS1, making SMARCA4 mutated cancers a clinically unmet disease. We have identified PRT3789, a potent and selective SMARCA2 degrader, that selectively targets SMARCA4-deficient cancer cells. In the present studies, we discuss the mechanism and activity of PRT3789 in SMARCA4-deficient tumor models as well as our clinical methods to assess target engagement in PRT3789 treated patients. PRT3789 is a bifunctional small molecule comprised of a novel SMARCA2-bromodomain binder linked to a VHL E3 ubiquitin ligase-binding moiety. PRT3789 has been shown to effectively catalyze the polyubiquitination of specific lysine residues of SMARCA2, resulting in SMARCA2 selective degradation over SMARCA4. The selectivity of PRT3789-induced SMARCA2 degradation was confirmed by cellular assays, protein mass spectrometry as ...