Rational Targeting of Oncogenic Kras and Sos Interaction in JMML
Abstract
KRAS mutations are particularly prevalent in childhood leukemia, including juvenile myelomonocytic leukemia, and in three major solid tumors, lung, pancreatic, and colon cancers. KRAS mutations often associate with resistance to chemotherapy/radiation therapy and significantly shorter survival. Therefore, how to selectively target oncogenic KRAS signaling becomes the primary focus of NCI RAS initiative and the holy grail in the RAS biology field. Our study identified a novel drug lead that targets oncogenic Kras and Sos interaction. Unlike previous FDA-approved drugs that target KRAS downstream proteins in both normal cells and cancer cells and thus have inherent toxicities, our compound only targets leukemia cells expressing the disease driver, oncogenic KRAS, while spares normal cells. In contrast to there cent development of KRAS inhibitors that only target one specific KRAS mutation and thus 13% of KRAS cancers, our Sos1 inhibitor approach inhibits the interaction between oncogenic Kras (regardless of oncogenic mutation residues) and Sos family members. In this application, we will further improve the potency of our compound by medicinal chemistry and test its usefulness in both mouse model and human patient leukemia cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2021
- Accession Number
- AD1154921
Entities
People
- Jing Zhang