Abstract title | SAT-122, a potential first-in-class, potent, small-molecule disruptor of RAD51-BRCA2, attenuates RAD51 foci formation and tumor progression in preclinical models |
Poster number | FPN: 35P |
Publication category | Basic science |
Session date and time | Sunday, October 22 | 9:00 am-5:00 pm |
Session location | Hall 8 |
Abstract title: SAT-122, a potential first-in-class, potent, small-molecule disruptor of RAD51-BRCA2, attenuates RAD51 foci formation and tumor progression in preclinical models
Abstract:
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 starting 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.
