Dhirendra Simanshu

Dr. Dhirendra Simanshu (Simanshu) leads the Structural Biology group at the NCI RAS Initiative, Frederick National Laboratory. His group investigates the structure and function of RAS proteins and their interactions with key effectors and regulators, focusing on structure-guided drug discovery targeting RAS-driven cancers. Their work has advanced understanding of RAS signaling, including structural insights into KRAS interaction with the cysteine-rich domain (CRD) of RAF1 (Nat Commun, 2020) and the PI3Kα–KRAS complex (Nat Commun, 2025). They defined the architecture of the SHOC2–MRAS–PP1C complex and its role in RAF activation (NSMB, 2022). His group solved the first structure of full-length prenylated KRAS (PNAS, 2016), providing insight into the hypervariable region, and recently characterized the understudied KRAS4A isoform (Sci Adv, 2023). Their structure-guided work contributed to the development of the KRAS-G12C dual (on/off) inhibitor BBO-8520 (Cancer Discov, 2025), now in clinical trials. In collaboration with Daiichi-Sankyo, they elucidated the structural basis of insulin mimetics that promote RAS–PI3Kα interaction (Science, 2025). In partnership with BridgeBio Oncology Therapeutics, they contributed to the development of the PI3Kα–RAS breaker BBO-10203 (Science, 2025), also in clinical evaluation.