A major challenge in drug development is to predict clinical response from resea

Question

A major challenge in drug development is to predict clinical response from research in the lab or in animal:s Drug development for cancer therapy, depends on two intertwined objectives; A drug must bind to its target protein with a low Ke so that the amount of drug that must be administered to the patients is kept in a reasonable range. Concentration at which drug a drug affects its intended target protein should be 10-100 fold lower than the concentration at which it affects off-target proteins a. b. Protein kinases are key components in the signaling pathways that control cell behavior, they have been intense targets for anticancer drug development. Results of high through put screening for kinase inhibitors are shown in the figure below and are represented schematically on an evolutionary tree of human kinases (so called human kinome) RTK RTK RTK TK TK 1 nM TKL TKL TKL TKL 10 nM CLK- ???? CLK CK MAP CLK ?? ???? CL CK MAP CK 100 nM CDK CDK CDK CDK PKA PKA PKA PKA 1 HM CAMK CAMK CAMK MK Gleevec BIRB-796 Iressa Staurosporine Binding affinities are represented in circles overlaid on position of target kinase on the kinome, with larger circles indicating low Ko values. A. Rank order of inhibitors from most specific to least specific. B. Binding of BIRB-796 appears to be clustered in a few regions of kinome. Why?

Explanation / Answer

A. most specific = least number of circles; as it will target smaller number of kinases.

therefore, order is :-

Iressa___Gleevec___BIRB-796___Staurosporine

B. Binding is clustered in few regions of kinome for BIRB-796 because it is selective towards that class of kinases only. Specifically, BIRB-796 binds to p38 MAPK kinases only.

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