35P - SAT-122: A potential first-in-class, potent, small-molecule disruptor of RAD51-BRCA2, attenuates RAD51 foci formation and tumor progression in preclinical models

Background

The DNA damage repair pathway plays a crucial role in signalling for effective DNA repair and cell cycle progression. DNA double-strand breaks (DSBs) are primarily repaired by homologous recombination. Acting downstream of ATR, ATM and PARP, RAD51 is a central recombinase in HR-mediated DDR pathway that participates in DSB repair via interaction with BRCA2, followed by its nuclear translocation. RAD51:BRCA2 interaction disruptors represent a first-in-class anticancer target with therapeutic potential in refractory solid tumors.

Methods

Binding of SAT-122 to RAD51 and its interaction with BRC4 was determined using Surface Plasmon Resonance (SPR) and pull-down of the RAD51:BRC4 complex, respectively. Downstream modulation of RAD51 and gamma H2AX foci, along with effect on cell cycle was studied. Antiproliferative effects of SAT-122 was evaluated in a panel of multiple solid tumor cell lines. Selectivity was evaluated in a kinase panel. Nanostring based evaluation of pathway-related genes following incubation of cells with SAT-122 was conducted. In Vivo efficacy was evaluated in NCI-H358 and MDA-MB-231 xenograft models.

Results

SAT-122 binds to RAD51 and disrupts RAD51:BRCA2 interaction with an IC₅₀ of 20 nM. Fluorescent microscopy studies indicated a dose dependent reduction of RAD51 foci, and an increase in g-H2AX foci at 500 nM. FACS analysis demonstrated arrest at late S and G2 phase with subsequent apoptosis. SAT-122 inhibited proliferation of over 30 different cancer cell lines at IC₅₀ranging from 150-800 nM. Biochemical selectivity was established against a 345-kinase panel. RNA seq studies suggested modulation of multiple genes in the homologous recombination repair (HRR) pathway in line with the mechanism. In vivo translation was confirmed in NCI-H358 and MDA-MB-231 xenograft models with TGI of >70% and 50%, respectively. Pharmacokinetic studies and tolerability studies in rodents, revealed sufficient exposures, along with a wide therapeutic window.

Conclusions

SAT-122 is a novel and potent disruptor of RAD51:BRCA2 with potential to be used in the DDR context, in solid tumors. IND-enabling studies are ongoing with clinical trials planned in H1 2024.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Satyarx Pharma Innovations Pvt Ltd.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.