Related Experiment Video

Updated: Aug 15, 2026

Assessing Cellular Target Engagement by SHP2 (PTPN11) Phosphatase Inhibitors
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
PubMed

Insights

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.

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