Related Experiment Video
Updated: Aug 15, 2026
08:45
Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
Published on: July 17, 2020
Discovery and Preclinical Characterization of I-0436650, a Selective SHP2 Allosteric Inhibitor for RAS-Driven Cancers
Alina Ciammaichella1, Francesca Puca1, Danilo Fabbrini1
1IRBM S.P.A. Via Pontina Km 30.600, 00071PomeziaRome, Italy.
Journal of Medicinal Chemistry
|August 13, 2026
Summary
A novel allosteric inhibitor, I-0436650, effectively targets SHP2 (Src homology 2 (SH2)-containing protein tyrosine phosphatase 2) phosphatase activity. This compound shows promise in preclinical models for treating cancers driven by specific signaling pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- SHP2 (Src homology 2 (SH2)-containing protein tyrosine phosphatase 2) is a critical regulator of cell signaling pathways.
- Dysregulation of SHP2 is implicated in various pathological processes, including cancer.
Purpose of the Study:
- To identify and characterize a novel allosteric inhibitor of SHP2.
- To evaluate the preclinical efficacy of the identified inhibitor in cancer models.
Main Methods:
- Structure-based drug design and optimization.
- In vitro biochemical and cellular assays to assess SHP2 inhibition and downstream effects.
- In vivo xenograft studies to evaluate anti-tumor efficacy.
Main Results:
- Identification of I-0436650, a potent, low-nanomolar allosteric inhibitor of wild-type SHP2.
- I-0436650 effectively inhibits ERK phosphorylation and exhibits antiproliferative activity in EGFR- and RAS-dependent cell lines.
- Single-agent administration of I-0436650 suppressed tumor growth, and combination therapy delayed tumor relapse in preclinical models.
Conclusions:
- I-0436650 demonstrates significant preclinical anti-cancer activity through SHP2 inhibition.
- Vertical inhibition strategies combining I-0436650 with pathway-specific inhibitors show potential for overcoming resistance and improving treatment outcomes.
Related Concept Videos
02:23Abnormal Proliferation
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
01:20The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...
01:24Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
03:03mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...