Simanshu Dhirendra

Group lead (Structural Biology) at NCI RAS Initiative @FredNatLab; RAS/RAF/PI3K structural biology and drug discovery

[Simanshu Dhirendra @simanshu]

In this review, we revisit this framework and propose that RAS family members exhibit intrinsic effector preferences, pointing to a more specialized and organized signaling network that reflects a more structured division of labor within the network.

[Simanshu Dhirendra @simanshu]

Our new review titled "Revisiting RAS family GTPase signaling: effector selectivity and oncogenic bypass," published today in the @Biochem_Journal Journal, published by the @BiochemSoc Society, and co-authored with @frankpmccormick

https://t.co/x0ygj4oNnx

[Simanshu Dhirendra @simanshu]

Historically, the canonical RAS proteins—KRAS, HRAS, and NRAS—have been viewed as the primary drivers of signaling, with their GTP-bound forms assumed to uniformly activate all major downstream effector pathways at the plasma membrane. But is this model too simplistic?

[Pau Castel @castel_pau]

Excited to share our latest work onll LZTR1 just published @ScienceMagazine!! A wonderful multidisciplinary collaboration between @simanshu's lab and our lab that provides structural understanding on RAS substrate and nucleotide specificity, and effect of mutations in LZTR1.

[Simanshu Dhirendra @simanshu]

BBO-10203 is currently being evaluated in the Phase 1 BREAKER-101 trial (NCT06625775) in patients with HER2+ and HR+/HER2- breast cancer, KRAS mutant colorectal cancer, and KRAS mutant non-small cell lung cancer.

[Simanshu Dhirendra @simanshu]

We are excited to share our collaborative work on the first-in-class RAS:PI3Kα breaker, BBO-10203, which has now been published online in @ScienceMagazine !

🔗 Read the full article here: https://t.co/pUvLXbdXJp

BridgeBio Oncology Therapeutics (BBOT) @FredNatLab @Livermore_Lab

[Simanshu Dhirendra @simanshu]

This publication describes how BBO-10203 disrupts the RAS–PI3Kα interaction without impairing insulin signaling, resulting in broad antitumor activity across multiple cancer models. It also shows enhanced efficacy in combination with other targeted agents.

[Simanshu Dhirendra @simanshu]

This work was led by Daniel Czyzyk and Wupeng Yan in the laboratory, in collaboration with RAS Initiative colleagues and researchers at Daiichi Sankyo.

[Simanshu Dhirendra @simanshu]

Excited to share our latest research, "Structural Insights into Isoform-Specific RAS-PI3Kα Interactions and the Role of RAS in PI3Kα Activation," now published in @NatureComms

📖 Explore the full article here:
https://t.co/iK6G45LDry

@FredNatLab

[Simanshu Dhirendra @simanshu]

Our findings reveal key interaction interfaces and isoform-specific differences in RAS-PI3Kα, highlighting its crucial role in activating the PI3K-AKT-mTOR pathway and providing a blueprint for designing isoform-specific inhibitors to target RAS- and PI3K-driven cancers.

[Simanshu Dhirendra @simanshu]

Our structural-guided insights contributed to the design of BBO-8520, a first-in-class dual inhibitor targeting both GTP-bound (ON) and GDP-bound (OFF) KRAS G12C.
Excited to see this work now published in @CD_AACR! @FredNatLab @BridgeBioPharma

[Elizabeth McKenna @ElizSMcKenna]

Now online in @CD_AACR: Discovery of BBO-8520, a First-in-Class Direct & Covalent Dual Inhibitor of GTP-Bound (ON) & GDP-Bound (OFF) KRAS G12C - by Anna Maciag, James Stice, Bin Wang, @frankpmccormick, Pedro Beltran, et al. https://t.co/jzMFwnuRPv @FredNatLab @BridgeBioPharma

[Simanshu Dhirendra @simanshu]

@ktr_nakanishi Congratulations @ktr_nakanishi and @futianmin! 👏👏

[Molecular Cell @MolecularCell]

Online Now: Functional and structural insights into RAS effector proteins https://t.co/Ak5smjbR0i

[Pau Castel @castel_pau]

Check out our latest review regarding the biology of RAS GTPase effectors!

It was fun to write this with @AmMozzarelli and @simanshu for @MolecularCell.

Bottom line: lots of knowledge on these proteins, but many questions that remain to be answered.

https://t.co/TeJFo27Buq

[Simanshu Dhirendra @simanshu]

@ktr_nakanishi @OSU_CBC @OSU_RNA Congratulations Kotaro!🎉🥂

[Simanshu Dhirendra @simanshu]

@ktr_nakanishi @OhioState @OSU_CBC @OSU_RNA Congratulations Kotaro!🎉

[AACR @AACR]

The three-part New Drugs on the Horizon Series at the AACR Annual Meeting 2024 wrapped up this morning. A total of 12 first-time disclosures were presented.
https://t.co/iA1MWHydq2
#AACR24

[Simanshu Dhirendra @simanshu]

The collaborative work was led by Lorenzo Finci, Mayukh Chakravarti, Gulcin Gulten, @dailyusbalius, @domespo and other members of the RAS initiative @FredNatLab

[Simanshu Dhirendra @simanshu]

Our latest work in ⁦@CommsBio⁩ describes the cryo-EM structure of the RAF1-HSP90-CDC37 complex. Insights from 1μs simulations and structural analysis reveal key interactions and the role of HSP90 and CDC37 in client folding. ⁩ https://t.co/4CnCJYhCiH

[Simanshu Dhirendra @simanshu]

Our work builds on previous structural studies by many other groups describing structures of HSP90 and CDC37 in complex with RAF1, or in complex with BRAF-V600E, with and without protein phosphatase 5.