On September 7, 2024 an impressive research study that may help treat several cancers was presented during the ASDRP Summer 2024 Research Symposium and Exposition. A research study led by Edward Njoo, Ph.D. (Stanford University), ASDRP's Director of Research and Chair of the Department of Chemistry and Biochemistry and his student researchers, involved a series of trials with more successful ways to target and treat cancer, specifically by targeting G12C Mutant KRAS which is found in a significant portion of cancers. It was previously considered untreatable but recent studies have made significant headway on the treatment of these cancers. The Njoo Research Group and ASDRP student researchers continued this recent advancement with their own research, by finding ways to utilize compounds that had a higher success rate than the reported yield, and was successfully selective in targeting G12C KRAS.
The Abstract by the Njoo Research Group
Oncogenic mutations in the GTPase protein KRAS are implicated in approximately 25% of human cancers. Specifically, the G12C mutation, a common mutation found in KRAS-related pathology, is found in 12% of non-small cell lung cancers and 3% of colorectal and other solid tumors. This single residue substitution causes irreversible binding of GTP/GDP to the catalytic site, thereby forcing the protein into a permanent, activated state. While KRAS has been previously considered an undruggable chemotherapeutic target, the discovery of acrylate-based covalent inhibitors of G12C KRAS has led to the development of two FDA-approved drugs: Sotorasib (AMG-510) and Adagrasib (MRTX849) which inspired our own pharmacophore model, and our library of isoxazole-based covalent inhibitors of G12C KRAS. En route, we optimized a previously reported amide coupling in which our library of analogs exhibited a comparatively higher yield of 98%. This transformation tolerates air with a trivial loss of yield and has been applied to 12 different examples of arylmethyl isoxazole acids and alkyl substituted piperazines including the synthesis of Nucleozin, in which our optimized conditions exhibited a yield of 78% as compared to the literature-reported yield of 43%. In vitro potency was then evaluated through MTT assays against Calu-1 cancer cell lines, and to test the selectivity, against HCT-116 cancer cell lines. Our S-methyl compounds were shown to be selective in targeting mutant G12C, as they were ineffective in HCT-116 colon cells, and our lead compound in specificity amongst these contains a 2,6-dichloroaryl ring. All completed by the Njoo Lab and ASDRP student researchers.
Authors & ASDRP student researchers
Natalie Brahan, Irvington High School '25; Sabrina Chau, Archbishop Mitty High School '28; Arshia Desarkar, Saratoga High School '25; Sahasra Gunturi, Dougherty Valley High School, Lutecia Lam, BASIS Independent Silicon Valley, Zoe Lin, Homestead High School '25; Vera Lin, BASIS Independent Fremont '25; Edward Njoo, Ph.D., ASDRP Director of Research.
The Njoo Reseach Laboratory and his student researchers continue to impress and they will be attending and presenting at the 2024 Southern California Conference for Undergraduate Research on November 23, 2024.
Comments