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

Abstract

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 well as ex vivo treatment of human PBMCs. PRT3789 selectively inhibits cell proliferation of SMARCA4-deficient cancer cells, but not SMARCA4 WT cells, when tested in a panel of cancer cell lines. Cell lines with specific SMARCA4 missense mutations also responded to PRT3789, suggesting that they are LOF mutations. Mechanistically, degradation of SMARCA2 leads to disruption of SWI/SNF complexes, dysregulation of chromatin remodeling and gene expression, resulting in inhibition of oncogenic pathways such as cell-cycle and DNA replication gene signatures. After treatment with PRT3789, SMARCA4-deleted cancer cells undergo G1 cell-cycle arrest and apoptosis. In vivo efficacy studies were conducted with genomically selected cell line-derived and patient-derived NSCLC xenograft models in mice. PRT3789 administration significantly inhibits the growth of SMARCA4-deleted NSCLC but demonstrates no effects on SMARCA4 WT tumor growth. In preclinical models, the effects on tumor growth were synergistic when PRT3789 was combined with other SOC therapies including gemcitabine, docetaxel, KRAS G12Ci as well as investigational drug candidates such as MCL1i, CDK4/6i, and CDK9i. PRT3789 also showed combination effects with anti-PD1 mAb in efficacy models in vivo. In the first-in-human Phase I dose-escalation study, PRT3789 target engagement will be assessed by determining the levels of SMARCA2 protein in human PBMCs following treatment with PRT3789. We aim to further investigate the safety, pharmacokinetics (PK) as well as anti-tumor activity of PRT3789 in the ongoing clinical trial (NCT05639751). Citation Format: Koichi Ito, Michael Hulse, Anjana Agarwal, Jack Carter, Monisha Sivakumar, Komali Vykuntam, Min Wang, Miles Cowart, Joy Cote, William Gowen-MacDonald, Brian Vidal Torres, Justin Kurian, Neha Bhagwat, Norman Fultang, Alexander Grego, Andrew Moore, Ashley Schwab, Jessica Burtell, Olusola Peace Osinubi, Jacob Spruance, Liang Lu, Philip Pitis, Corey Basch, Klare Bersch, Chaofeng Dai, Raul Leal, Artem Shvartsbart, Ganfeng Cao, Bo Shen, Patrick Wen, Joseph Rager, Ross Kuskovsky, Bob Landman, Tom Emm, Stefan Ruepp, Chunhua Qin, Gina Paris, Jennifer Xavier, Rachel Chiaverelli, Sang Hyun Lee, Sandy Geeganage, Hong Lin, Diane Heiser, Bruce Ruggeri, Naveen Babbar, Andrew Combs, Peggy Scherle. Discovery of PRT3789, a first-in-class potent and selective SMARCA2 degrader in clinical trials for the treatment of patients with SMARCA4 mutated cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B113.