AU-15330

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.

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.

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.

The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells...Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M up-regulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors.

Our study found that the mechanisms of resistance of PROTAC degraders can vary and may be dependent on drug concentrations. Such concepts may inform future clinical decision-making regarding drug dosing.