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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors

R Kumar1, M-C Crouthamel, D H Rominger

  • 1Cancer Research, GlaxoSmithKline, Collegeville, PA 19426, USA. rakesh.2.kumar@gsk.com

British Journal of Cancer
|October 22, 2009
PubMed
Abstract

Insights

Differences in myelosuppression from multikinase angiogenesis inhibitors like pazopanib, sorafenib, and sunitinib may be explained by their varying activity against c-kit and Flt-3 kinases.

Area of Science:

  • Pharmacology
  • Oncology
  • Molecular Biology

Background:

  • Myelosuppression is a known side effect of multikinase angiogenesis inhibitors.
  • The specific kinases inhibited by these drugs, beyond VEGFR, may influence their adverse event profiles.

Purpose of the Study:

  • To compare the kinase selectivity and cellular potency of pazopanib, sorafenib, and sunitinib.
  • To investigate the impact of kinase inhibition on human bone marrow progenitor cell growth.

Main Methods:

  • Evaluated kinase selectivity across a panel of 242 kinases.
  • Assessed cellular potency using autophosphorylation assays.
  • Determined effects on bone marrow progenitor growth in response to various growth factors.

Main Results:

  • Sunitinib inhibited more kinases than pazopanib and sorafenib.
  • All three drugs potently inhibited VEGFR-2, PDGF-R-beta, and c-Kit.
  • Pazopanib showed less activity against Flt-3; drug effects on bone marrow cells varied with growth factors.

Conclusions:

  • Differential activity against c-kit and Flt-3 may explain varying myelosuppression.
  • Understanding kinase selectivity is crucial for predicting and managing side effects of angiogenesis inhibitors.

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