Reference Detail

Ref Type

abstract

PMID

Authors

Artem Shvartsbart; Koichi Ito; Joseph Rager; Michael Hulse; Anjana Agarwal; Komali Vykuntam; Jessica Burtell; Min Wang; Justin Kurian; Miles Cowart; Joy Cote; Nick Stahl; Monisha Sivakumar; Anthony Reichelderfer; Jack Carter; Alexander Grego; Andrew Moore; Neha Bhagwat; Ross Kuskovsky; Shanthi Ganesan; Stefan Ruepp; Tom Emm; Philip Pitis; Corey Basch; Klare Bersch; Yongchun Pan; Song Mei; Raul Leal; John Rose; Dani Roth; Chaoyi Xu; Ganfeng Cao; Kris Vaddi; Sang Hyun Lee; Sandy Geeganage; Andrew Combs; Peggy Scherle

Title

Abstract 4503: Preclinical characterization of PRT7732: A highly potent, selective, and orally bioavailable targeted protein degrader of SMARCA2

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer Researc	84	6_supplement	March 15, 2024

URL

https://aacrjournals.org/cancerres/article/84/6_Supplement/4503/740602

Abstract Text

SWI/SNF (BAF) 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, containing an ATPase domain and a bromodomain. SMARCA4 protein expression is lost in some cancers due to loss-of-function (LOF) mutations and homozygous deletions, and SMARCA4-deleted cancer cells are highly dependent on its paralog gene SMARCA2 for their survival. Therefore, targeting SMARCA2 in SMARCA4-deficient cancers using selective SMARCA2 degraders induces synthetic lethality while sparing SMARCA4 wild type (WT) normal cells. We have recently identified a series of orally bioavailable SMARCA2 selective degraders that demonstrate robust efficacy in pre-clinical animal models with favorable pharmacokinetic properties and safety profiles. Our nomination candidate PRT7732 exhibits >1000x selectivity for SMARCA2 over SMARCA4 in cell-based assays, with DC50 values in cancer cell lines in the low nanomolar range. The PRT7732-induced SMARCA2 degradation was rescued by a proteasome inhibitor and neddylation inhibitor, indicating ubiquitin-proteasome dependent degradation. Furthermore, PRT7732 does not change levels of known CRBN ligand neo-substrates such as IKZF2/3, GSPT1 and SALL4. PRT7732 inhibits only SMARCA4-deficient cancer cell proliferation with IC50 values ranging from 5.0-50 nM, but not SMARCA4 WT cells in vitro. Oral administration of PRT7732 resulted in near-total degradation of SMARCA2 protein with complete selectivity over SMARCA4 protein in a SMARCA4 WT lung cancer model in mice, consistent with the SMARCA2 degradation kinetics-based pharmacodynamic prediction model. PRT7732 oral daily administration showed significant tumor growth inhibition of SMARCA4-deficient lung cancer xenograft models at well tolerated doses. The treated tumor tissues show robust SMARCA2 protein reduction for 24h post dosing. In summary, our orally bioavailable SMARCA2 degraders induce synthetic lethality in SMARCA4-deficient cancers in vitro and in vivo. Efforts to further evaluate these compounds in additional models and in combination with other agents are ongoing.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
PRT7732	PRT7732	2	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PRT7732		PRT-7732\|PRT 7732		PRT7732 is a Smarca2 degrader, which potentially inhibits tumor growth (Cancer Res (2024) 84 (6_Supplement): 4503).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
SMARCA4 loss	lung cancer	predicted - sensitive	PRT7732	Preclinical	Actionable	In a preclinical study, PRT7732 inhibited tumor growth in a SMARCA4-deficient lung cancer xenograft model (Cancer Res (2024) 84 (6_Supplement): 4503).	detail...
SMARCA4 loss	Advanced Solid Tumor	predicted - sensitive	PRT7732	Preclinical - Cell culture	Actionable	In a preclinical study, PRT7732 inhibited proliferation of SMARCA4-deficient cancer cell lines in culture (Cancer Res (2024) 84 (6_Supplement): 4503).	detail...