Related Experiment Video

Updated: Oct 23, 2025

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

6.4K

Targeted Degradation of the Oncogenic Phosphatase SHP2

Vidyasiri Vemulapalli1,2, Katherine A Donovan2, Tom C M Seegar3

  • 1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States.

Biochemistry
|August 19, 2021
PubMed

Insights

Researchers developed a novel SHP2 PROTAC to degrade the SHP2 protein, a key driver in cancers. This new molecule effectively inhibits cancer cell growth and offers a promising alternative to current SHP2 inhibitors.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • SHP2 protein tyrosine phosphatase is crucial for Ras-MAPK pathway activation.
  • SHP2 alterations are implicated in human cancers and developmental disorders.
  • Existing SHP2 allosteric inhibitors are in clinical trials.

Purpose of the Study:

  • To develop and evaluate a novel SHP2 PROTAC (proteolysis-targeting chimera).
  • To assess the efficacy of the SHP2 PROTAC in degrading SHP2 and inhibiting cancer cell growth.

Main Methods:

  • Conjugation of RMC-4550 with pomalidomide via a PEG linker to create the SHP2 PROTAC.
  • Evaluation of SHP2 degradation in leukemic cells.
  • Assessment of MAPK signaling inhibition and cancer cell growth suppression.

Main Results:

  • The developed SHP2 PROTAC demonstrated high selectivity for SHP2.
  • Submicromolar concentrations of the PROTAC induced SHP2 degradation in leukemic cells.
  • The molecule effectively inhibited MAPK signaling and suppressed cancer cell proliferation.

Conclusions:

  • SHP2 PROTACs represent a viable strategy for targeting ERK-dependent cancers.
  • This SHP2 PROTAC is a valuable tool for studying SHP2's oncogenic mechanisms.
  • SHP2 PROTACs offer an alternative therapeutic approach alongside allosteric inhibitors.

More Related Videos

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases06:56

Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

Published on: September 6, 2024

523
Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes09:40

Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes

Published on: September 28, 2018

15.3K

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The 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...
9.6K
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
14.2K
Protein Kinases and Phosphatases02:54

Protein Kinases and Phosphatases

Proteins undergo chemical modifications that trigger changes in the charge, structure, and conformation of the proteins. Phosphorylation, acetylation, glycosylation, nitrosylation, ubiquitination, lipidation, methylation, and proteolysis are various protein modifications that regulate protein activity. Such modifications are usually enzyme-driven.
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
13.9K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
4.2K
Abnormal Proliferation02:23

Abnormal 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...
4.7K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.0K