Abstract 1578: Novel Cereblon mediated bifunctional degraders of SOS1 for treatment of pan-KRAS mutant tumors

KRAS, a GTPase that regulates cellular growth, is the most frequently mutated oncogene with implications in non-small cell lung, pancreatic and colorectal cancers. Hyperactivation of KRAS in mutant alleles favors KRAS in its active GTP-bound state over its inactive GDP-bound state. Once deemed undruggable, recent advances have revealed promising anti-tumor effects with pan-KRAS and KRAS-mutant specific inhibitors in both preclinical and clinical settings. Despite the success of these inhibitors, the diversity of tumors as well as tumor sensitivity results in acquired drug resistance suggesting that combinational therapeutic approaches would be necessary to avoid this problem. An attractive dual approach would be to couple KRAS inhibition with a blockade of its guanine exchange factor (GEF), SOS1, to keep KRAS in its inactive state as well as prevent upstream pathway reactivation. Utilizing our PRODEGY platform, we developed bifunctional SOS1 degraders for the treatment of patients with KRAS mutant cancers. These degraders have shown rapid and potent Cereblon (CRBN)-mediated degradation which exhibit DC50s