Title

DISCOVERY OF MUTANT SELECTIVE PLATELET DERIVED GROWTH FACTOR RECEPTOR (PDGFR) FAMILY KINASE INHIBITORS

Introduction

In the past decade there has been rapid growth in the number of FDA approved cancer drugs within the class known as kinase inhibitors. Some kinase inhibitors have become first line chemotherapy for certain tumor types. For example, imatinib (Gleevec) is used effectively to treat Ph+ chronic myelogenous leukemia. Unfortunately, resistance to kinase inhibitors can develop through upregulation of, or mutation of the target kinase resulting in decreased drug binding.

Purpose

This project is aimed at the evaluation of new molecules designed to be kinase inhibitors, including cancer relevant mutant forms, and their effectiveness against tumor cell proliferation.

Method

We used tumor cell based screening to evaluate the potential of new molecules to inhibit tumor cell growth using both SRB and MTT based assays. We used commercial services to screen active compounds for both binding to an inhibition of function of kinase enzymes, including cancer relevant mutant forms. We also evaluated the stability of identified lead molecules to metabolism in human liver microsomes (HLM).

Results

The initial cell based screening identified two different designed chemotypes with the ability to inhibit cancer cell growth, represented by molecules Q-12 and Q-18. Molecule Q-12 was determined to compete with ATP for binding to and inhibit the function of cancer relevant mutant PDGFR family kinases. Furthermore Q-12 inhibited the proliferation of cell lines dependent on mutant KIT (PDGFR family member) kinases for survival. Molecule Q-18 inhibits select kinases, not including PDGFR family kinases, only modestly. Despite Q-18’s impressive antitumor cell activity, a convincing kinase target has yet to be identified. Molecule Q-12 is more stable to HLM than Q-18.

Significance

Because one of the major mechanisms of resistance to kinase inhibitors is the revelation of tumor cells expressing a mutant target kinase, there is a need for inhibitors effective against these mutants. Additionally drug molecules that selectively inhibit cancer relevant mutant kinases relative to wild-type kinases expressed in normal tissue, these drugs may have a better side-effect and safety profile compared to non-selective inhibitors. Furthermore, the progression of personalized cancer medicine is making more routine genotyping of tumors to better match patients with drugs that are more likely to be effective based on the patients’ tumor mutation profile. The mutant kinase selectivity of Q-12 is attractive in light of the above realizations.

Location

DeRosa University Center, Stockton campus, University of the Pacific

Format

Poster Presentation

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Mar 25th, 10:00 AM Mar 25th, 3:00 PM

DISCOVERY OF MUTANT SELECTIVE PLATELET DERIVED GROWTH FACTOR RECEPTOR (PDGFR) FAMILY KINASE INHIBITORS

DeRosa University Center, Stockton campus, University of the Pacific

In the past decade there has been rapid growth in the number of FDA approved cancer drugs within the class known as kinase inhibitors. Some kinase inhibitors have become first line chemotherapy for certain tumor types. For example, imatinib (Gleevec) is used effectively to treat Ph+ chronic myelogenous leukemia. Unfortunately, resistance to kinase inhibitors can develop through upregulation of, or mutation of the target kinase resulting in decreased drug binding.