Dhirendra Simanshu

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Dhirendra K Simanshu
Born
India
Other namesSimanshu
CitizenshipAmerican (naturalized)
Scientific career
FieldsStructural Biology
InstitutionsNCI RAS Initiative, Frederick National Laboratory for Cancer Research

Dhirendra K. Simanshu is an Indian-American structural biologist and a group leader at the National Cancer Institute's (NCI) RAS Initiative at the Frederick National Laboratory for Cancer Research..[1] His research focuses on the structural and biochemical characterization of oncogenic RAS mutants and their interactions with regulatory and effector proteins, including RAF, PI3K, GTPase-activating proteins (GAPs), and trafficking proteins.[2] He has authored multiple research articles on RAS signaling and structure-based drug discovery.[3] His group has contributed to the development of targeted therapies for RAS-driven cancers, including investigational inhibitors such as BBO-10203 and BBO-8520, which are undergoing clinical trials.[4][5]

Education

Simanshu was born in India and earned a Bachelor’s degree in Biotechnology from St. Columba's College, Hazaribag.[6] He obtained a Master’s degree in Biotechnology from Jawaharlal Nehru University, New Delhi, followed by a Ph.D. from the Indian Institute of Science, where he studied the structure and function of metabolic enzymes under the supervision of M.R.N. Murthy.[7] He later conducted postdoctoral research at Memorial Sloan-Kettering Cancer Center in New York under the guidance of Dinshaw Patel, focusing on the structural analysis of lipid-transfer proteins and macromolecular complexes involved in RNA interference and toxin-antitoxin systems.[8][9]

Scientific Contribution

Simanshu joined the NCI RAS Initiative in 2014 as the group leader of the RAS Structural Biology Laboratory.[10] His work has contributed to the structural characterization of full-length prenylated KRAS with hypervariable region, providing insights into its interaction with trafficking proteins such as PDEδ[11]. His research on KRAS splice variants has identified structural differences influencing their functional properties[12]. Additionally, he has investigated RAS-effector interactions, including KRAS-RAF1 and SHOC2-MRAS-PP1C complexes, which are involved in RAS signaling and developmental disorders such as Noonan syndrome[13][14].

His group has also examined the role of RAS in PI3K activation, including the structure of KRAS in complex with PI3Kα[15]. Collaborative efforts with academic and industry partners have led to the development of small molecules targeting RAS-PI3Kα interactions, including the design of a molecular glue compound and a "breaker" disrupting these interactions.[16][17] He has authored numerous research and review articles and contributed book chapters, with over 75 publications listed on Google Scholar.[3][18]

Simanshu and his colleagues at the Frederick National Laboratory for Cancer Research, in collaboration with the International Space Station (ISS) National Laboratory, conducted a study using microgravity conditions to investigate the structure and dynamics of the KRAS protein, aiming to improve the development of targeted therapies for RAS-driven cancers.[19]

Awards and Recognition

Simanshu has received several awards for his research contributions. In 2023, he and his colleagues received the Best Publication Award in biomedical research from Leidos Biomedical Research.[20] He was awarded the Intermediate Fellowship from the DBT/Wellcome Trust India Alliance[21] and previously received the Young Scientist Medal from the Indian National Science Academy (2008)[22] and the Prof. Ratna Phadke Young Researcher Award from the Indian Biophysical Society (2007).[23]

References

  1. ↑ "Structural Biology Research on RAS Complexes - NCI". www.cancer.gov. 2015-04-30. Retrieved 2025-02-11.
  2. ↑ Nissley, Dwight V.; McCormick, Frank (2022-04-01). "RAS at 40: Update from the RAS Initiative". Cancer Discovery. 12 (4): 895–898. doi:10.1158/2159-8290.CD-21-1554. ISSN 2159-8274. PMID 35046096.
  3. ↑ 3.0 3.1 "Dhirendra Simanshu". scholar.google.com. Retrieved 2025-02-11.
  4. ↑ TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics (2025-01-23). "A Phase 1a/1b Study of the PI3Kα:RAS Breaker BBO-10203 in Subjects With Advanced Solid Tumors (The BREAKER-101 Study)". clinicaltrials.gov.{{cite web}}: CS1 maint: multiple names: authors list (link)
  5. ↑ "Clinical Trial NCI-2024-03040 – National Cancer Institute". www.cancer.gov. 2016-06-23. Retrieved 2025-02-11.
  6. ↑ "Face to Face with Dhirendra K Simanshu". Club SciWri. 2016-01-24. Retrieved 2025-02-11.
  7. ↑ "Welcome to Our Homepage". mbu.iisc.ac.in. Retrieved 2025-02-11.
  8. ↑ "Synapse - Dhirendra Simanshu". synapse.mskcc.org. Retrieved 2025-02-11.
  9. ↑ "The Dinshaw Patel Lab | Sloan Kettering Institute". www.mskcc.org. Retrieved 2025-02-11.
  10. ↑ "Structural Biology Research on RAS Complexes - NCI". www.cancer.gov. 2015-04-30. Retrieved 2025-02-11.
  11. ↑ Dharmaiah, Srisathiyanarayanan; Bindu, Lakshman; Tran, Timothy H.; Gillette, William K.; Frank, Peter H.; Ghirlando, Rodolfo; Nissley, Dwight V.; Esposito, Dominic; McCormick, Frank; Stephen, Andrew G.; Simanshu, Dhirendra K. (November 2016). "Structural basis of recognition of farnesylated and methylated KRAS4b by PDEδ". Proceedings of the National Academy of Sciences. 113 (44): E6766–E6775. Bibcode:2016PNAS..113E6766D. doi:10.1073/pnas.1615316113. ISSN 0027-8424. PMC 5098621. PMID 27791178.
  12. ↑ Whitley, Matthew J.; Tran, Timothy H.; Rigby, Megan; Yi, Ming; Dharmaiah, Srisathiyanarayanan; Waybright, Timothy J.; Ramakrishnan, Nitya; Perkins, Shelley; Taylor, Troy; Messing, Simon; Esposito, Dominic; Nissley, Dwight V.; McCormick, Frank; Stephen, Andrew G.; Turbyville, Thomas (2024-02-14). "Comparative analysis of KRAS4a and KRAS4b splice variants reveals distinctive structural and functional properties". Science Advances. 10 (7): eadj4137. Bibcode:2024SciA...10J4137W. doi:10.1126/sciadv.adj4137.
  13. ↑ Tran, Timothy H.; Chan, Albert H.; Young, Lucy C.; Bindu, Lakshman; Neale, Chris; Messing, Simon; Dharmaiah, Srisathiyanarayanan; Taylor, Troy; Denson, John-Paul; Esposito, Dominic; Nissley, Dwight V.; Stephen, Andrew G.; McCormick, Frank; Simanshu, Dhirendra K. (2021-02-19). "KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation". Nature Communications. 12 (1): 1176. Bibcode:2021NatCo..12.1176T. doi:10.1038/s41467-021-21422-x. ISSN 2041-1723. PMC 7895934. PMID 33608534.
  14. ↑ Bonsor, Daniel A.; Alexander, Patrick; Snead, Kelly; Hartig, Nicole; Drew, Matthew; Messing, Simon; Finci, Lorenzo I.; Nissley, Dwight V.; McCormick, Frank; Esposito, Dominic; Rodriguez-Viciana, Pablo; Stephen, Andrew G.; Simanshu, Dhirendra K. (October 2022). "Structure of the SHOC2–MRAS–PP1C complex provides insights into RAF activation and Noonan syndrome". Nature Structural & Molecular Biology. 29 (10): 966–977. doi:10.1038/s41594-022-00841-4. ISSN 1545-9993. PMC 10365013. PMID 36175670.
  15. ↑ Czyzyk, Daniel; Yan, Wupeng; Messing, Simon; Gillette, William; Tsuji, Takashi; Yamaguchi, Mitsuhiro; Furuzono, Shinji; Turner, David M.; Esposito, Dominic; Nissley, Dwight V.; McCormick, Frank; Simanshu, Dhirendra K. (2025-01-09). "Structural insights into isoform-specific RAS-PI3Kα interactions and the role of RAS in PI3Kα activation". Nature Communications. 16 (1): 525. Bibcode:2025NatCo..16..525C. doi:10.1038/s41467-024-55766-x. ISSN 2041-1723.
  16. ↑ TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics (2025-01-23). "A Phase 1a/1b Study of the PI3Kα:RAS Breaker BBO-10203 in Subjects With Advanced Solid Tumors (The BREAKER-101 Study)". clinicaltrials.gov.{{cite web}}: CS1 maint: multiple names: authors list (link)
  17. ↑ Beltran, Pedro; Dhirendra, Simanshu; Xu, Rui; Chen, Ming; Czyzyk, Daniel; Donovan, Sofia; Feng, Siyu; Feng, Cindy; Fu, Lijuan; Lightstone, Felice; Lin, Ken; Maciag, Anna; Nissley, Dwight; Riegler, Erin; Sinkevicius, Kerstin (2024-05-02). "Abstract RF02-02: BBO-10203, a first-in-class, orally bioavailable, selective covalent small molecule that inhibits RAS-driven PI3Kalpha activity without affecting glucose metabolism". Cancer Research. 84 (9_Supplement): RF02–02. doi:10.1158/1538-7445.SABCS23-RF02-02. ISSN 0008-5472.
  18. ↑ Simanshu, Dhirendra K.; Knox, John E. (2025), "The evolution of RAS structural biology", RAS Drug Discovery, Elsevier, pp. 119–143, doi:10.1016/b978-0-443-21861-3.00012-7, ISBN 978-0-443-21861-3, retrieved 2025-02-11
  19. ↑ wpadmin (2023-02-27). "Space Crystals and the Search for a Cancer Cure: Using Microgravity to Improve Protein Crystallization". ISS National Lab. Retrieved 2025-02-11.
  20. ↑ "Leidos scientists honored for technical research excellence | Leidos". www.leidos.com. Retrieved 2025-02-11.
  21. ↑ "India Alliance - Advancing Discovery & Innovation to Improve Health". www.indiaalliance.org. Retrieved 2025-02-11.
  22. ↑ https://insaindia.res.in/council/
  23. ↑ https://www.linkedin.com/in/dhirendra-simanshu-1426a52/

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