An Oncology biotech pioneering  RAD51 inhibition and other DDR mechanisms 

Satya to Highlight its SOS1 inhibitors that demonstrate best-in-class single agent activity in preclinical models of KRAS driven tumors at the Upcoming AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics – Oct 11-15, Boston, USA

 

Abstract title

Best in class, potent, SOS1 inhibitors demonstrate single agent activity in preclinical models of KRAS driven tumors

Poster number

A099

Session

Poster Session A                             

Session date and time

Thursday, October 12 | 12:30 pm-4:00 pm

Session location

Level 2, Exhibit Hall D

Abstract title: Best in class, potent, SOS1 inhibitors demonstrate single agent activity in preclinical models of KRAS driven tumors

Abstract:

KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). Interaction of KRAS with its predominant Guanine Exchange Factor (GEF), SOS1, is crucial for activation of KRAS and further KRAS mediated oncogenic signaling. Thus, pharmacological inhibition of SOS1 is expected to be effective in treating RAS driven cancers. Biochemical potency of compounds was confirmed in a SOS1 mediated FRET based guanine exchange factor (GEF) assay. Multiple potent SOS1 inhibitors were identified with potencies in the low double digit nanomolar range. Selectivity was determined against SOS2 and a host of other kinases in the RAS/RAF/MEK or RAS/PI3K/AKT pathways. Anti-proliferative activity across a panel of WT and mutant KRAS cell lines revealed IC50 between 50-200 nM with synergism observed when combined with MAPK pathway inhibitors as well as the KRAS G12C inhibitor, Sotorasib, in a 3D anchorage independent assay format. Correspondingly, significant reduction in PD biomarkers (>50% at 100 nM), pERK and pAKT, was demonstrated in KRAS mutant as well as EGFR/PI3K mutant cell lines. PK-PD correlation was also established in a tumor bearing mice model, with dose-dependent reduction of both pERK and pAKT. Compounds demonstrated excellent ADME properties with significant tissue distribution upon oral dosing. One of the lead molecules demonstrated significant single agent efficacy with growth inhibition of approximately 70% in a KRAS G12C bearing NSCLC xenograft model. No adverse signs including reduction in food intake or body weight loss were reported during the study period. IND-enabling studies are currently ongoing for the lead compounds.

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