We developed multiple MRD models both in vitro (rapamycin persistent, RP) and in vivo after mTORC1 inhibition. MYC and SWI/SNF expression was significantly enhanced. Both the SWI/SNF inhibitor AU-15330 and the mitochondrial complex I oxidative phosphorylation inhibitor IACS-010759 showed pronounced synergy with bi-steric mTORC1 inhibitors to cause cuproptotic cell death in RP/MRD cells, suggesting these combinations as a potential patient treatment strategy for rapalog resistance.

P1, N=42, Active, not recruiting, Prelude Therapeutics | Recruiting --> Active, not recruiting | N=104 --> 42

P1, N=135, Completed, Prelude Therapeutics | Active, not recruiting --> Completed | Trial completion date: Mar 2026 --> Oct 2025 | Trial primary completion date: Mar 2026 --> Oct 2025

Together, these findings demonstrate the selective targeting of SMARCA2 and the potential for a favorable therapeutic index with PRT3789. Phase I/II clinical trials with PRT3789 are ongoing in biomarker-selected patients with SMARCA4-mutated solid tumors.

P2, N=7, Active, not recruiting, Prelude Therapeutics | Recruiting --> Active, not recruiting | N=60 --> 7

Finally, BRM014 alone or in combination with olaparib also increased the frequency of micronuclei formation and activated the cGAS/STING response mediated by the activation of NFκB. Similar results were observed by inducing the degradation of both SWI/SNF ATPases by a PROTAC (AU-15330), which impaired the repair of DSBs, sensitized cells to DNA damage and PARPi. This study shows that inhibition or degradation of both SWI/SNF ATPases enhances the effects of chemotherapy, and activates the cGAS/STING response, which is associated with better therapeutic outcomes. This study shows that SWI/SNF chromatin remodelers are an important target to enhance the effects of chemotherapy and can affect the choice of DSB repair pathway.

The SMARCA4-specific PROTAC-degrader AU-15330 significantly reduced SOX11 binding to specific regulatory regions and diminished the activation of BCR-, NIK-, and BCL2-signaling pathways. Moreover, SMARCA4 degradation significantly reduced proliferation and induced apoptosis of SOX11-positive MCL cells, highlighting AU-15330 as a promising therapeutic approach for patients who may relapse from current target therapies in MCL.

P1, N=135, Active, not recruiting, Prelude Therapeutics | Recruiting --> Active, not recruiting | N=226 --> 135

P2, N=60, Recruiting, Prelude Therapeutics | Not yet recruiting --> Recruiting

SMD-3236 effectively inhibits tumor growth with weekly administration in the H838 SMARCA4-deficient human cancer xenograft model at well-tolerated dose schedules. SMD-3236 represents a promising SMARCA2 degrader for extensive evaluation as a new therapy for the treatment of SMARCA4-deficient human cancers.

The PROTAC degrader of SMARCA2/4 AU-15330 effectively abolished structures of cis-regulatory elements bound by CHD6 and suppressed the growth of FH-mutated, but not FH-intact, RCC in vivo. Collectively, these data indicate that CHD6 is a molecular bridge between FH deficiency and pro-inflammatory enhancers assembly that endows FH-deficient tumors with epigenetic vulnerabilities.

We further highlight the optimization of the pharmacokinetic profile of a subset of compounds leading to potent and selective degradation of SMARCA2 in the xenograft model. These compounds provide valuable tools with desirable properties for continued exploration of the biology defining the susceptibility of SMARCA4 mutant cancers to selective loss of SMARCA2.