Selective PROTAC-mediated degradation of SMARCA2 is efficacious in SMARCA4 mutant cancers

Abstract

The mammalian SWItch/Sucrose Non-Fermentable (SWI/SNF) helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of selective SMARCA2 inhibition is likely essential to afford an acceptable therapeutic index, and realizing this objective is challenging due to the homology with the SMARCA4 paralog. Herein we report the discovery of a potent and selective SMARCA2 proteolysis-targeting chimera molecule (PROTAC), A947. Selective SMARCA2 degradation is achieved in the absence of selective SMARCA2/4 PROTAC binding and translates to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling reveal no unexpected off-target degradation related to A947 treatment. Our study thus highlights the ability to transform a non-selective SMARCA2/4-binding ligand into a selective and efficacious in vivo SMARCA2-targeting PROTAC, and thereby provides a potential new therapeutic opportunity for patients whose tumors contain SMARCA4 mutations.

Discovery of a Selective and Orally Bioavailable FGFR2 Degrader for Treating Gastric Cancer

“…However, little or no CSF1R degradation was observed after LC-MB12 treatment at various concentrations. Thus, our findings verify that PROTAC transformation provides a promising strategy for converting multi-targeted inhibitors into selective or even isoform-selective degraders similar to that of other recently determined degraders: SMARCA2, 30 CDKs, 31 TRK, 32 and cMET. 33 However, the mechanism underlying the selective degradation of the FGFR2 isoform by LC-MB12 remains unclear.…”

Precise Conformational Control Yielding Highly Potent and Exceptionally Selective BRD4 Degraders with Strong Antitumor Activity

“…One of the very attractive features of a PROTAC degrader molecule is its ability to achieve high degradation selectivity for one protein over its closely homologous proteins. ,,,,− This is due to the fact that a PROTAC degrader must form a productive ternary complex consisting of the degrader itself, the protein of interest (POI), and an E3 ligase, to achieve effective degradation of the POI . The formation of the productive ternary complex may involve protein surface residues from both the POI and the E3 ligase. ,, In contrast to the conserved binding site residues in homologous proteins, protein surface residues are not well conserved even among highly homologous proteins.…”

A two-faced selectivity solution to target SMARCA2 for cancer therapy

“…Now, two recent papers from Kofink et al and Cantley et al have prospectively targeted the PROTAC-mediated ternary complex to solve the apparently intractable SMARCA2/4 selectivity problem 12 , 13 .…”

“…The second paper from Cantley et al describes a structurally distinct and highly potent SMARCA2-selective PROTAC A947 (Fig. 1b ) 13 . In this case, an alternative exit vector from the VHL E3 ligase binder was used, connected to a more advanced SMARCA2/4 ligand, similar to that used previously in ACBI1 14 .…”