(1318-C) Identification of compounds targeting KRAS and SHP2 from the National Cancer Institute diversity compound library with protein conformational array
Tuesday, February 6, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: KRAS and SHP2 plays important role during cancer development. Two Protein Conformational Array ELISAs was developed with 10 and 27 antibodies covering the whole KRAS and SHP2 molecule respectively. By measuring the linear epitope distribution on the surface of the KRAS and SHP2 protein, the conformational (Higher Order Structure or HOS) change induced by the screened compounds can be described quantitively. Both Direct ELISA and Sandwich ELISA were used for the screening of allosteric regulation compounds from the NCI Diversity Set compound library, multiple compounds capable of disrupting KRAS or SHP2 was identified. Further characterization of these compounds demonstrated that some of the hits are capable of multi-domain disruption for SHP2 or significant disruption of KRAS higher order structure. Antitumor activities have been demonstrated in both the NCI-60 cancer cell line potency testing and selected animal tumor models. The identification of compounds capable of disrupting multiple domains from the targets can also minimize the possible drug resistance issue arising from mutant selection during cancer treatment, offering an unique approach for allosteric regulation-based drug development. .