Transcript Overriding Imatinib Resistance with a Novel ABL Kinase

Gleevec vs. BMS-354825
Druker vs. Sawyers
Yashar Kalani
Biochemistry 230
Imatinib or Gleevec inhibitor
of BCR-ABL tyrosine kinase.
Binds to the ATP binding site
of BCR-ABL only when the
activation loop is closed and
thus stabilizes the protein in
an inactive conformation.
In addition, the normally
smooth contour of the
phosphate binding loop of
ABL is distorted by Gleevec
binding.
Produces clinical remission in
chronic myeloid leukemia
(CML) with minimal toxicity.
To date 17 mutations, mostly within the kinase domain of
BCR-ABL have been observed.
Most resistant form
Most frequently seen (20%)
Majority impair the ability of the kinase to adopt
specific closed conformation to which Gleevec
binds and some inhibit drug binding directly.
• A family of SRC-ABL inhibitors also bind
to the ATP-binding site in ABL, but without
regard for the position of the activation
loop; this highlights their potential use as
therapeutics.
• Inhibitor of SRC-family kinases.
• Competitive ATP inhibitor with broad spectrum
antiproliferative activity against hematological and
solid tumor cell lines.
• Based on structural insight from other dual SRCABL inhibitors, BMS-354825 was reasoned to
impose less stringent conformational requirements
on ABL for kinase inhibition.
• BMS-354825 was more potent than Gleevec
at inhibiting nonmutated BCR-ABL kinase
activity in a cell-based assay.
T315I Only resistant form
•Activity of 14 of 15 relevant resistant forms was
inhibited in the low nanomolar range.
• Growth of Ba/F3 cells expression various
isoforms was also inhibited.
• To assess its potential as a therapeutic, a
SCID mouse model of Gleevec resistance
was used.
• Mice injected with Ba/F3 cells expressing
different mutants (tagged with luciferase
gene).
• WT and mutant forms appeared healthy with no
evidence of weight loss, lethargy or ruffled fur and
showed greater than one log lower levels of
bioluminescent activity two weeks after therapy.
Conclusions
• The primary consequence of all ABL kinase
domain mutations associated with Gleevec
resistance is the impairment of kinase domain
flexibility such that the kinase domain is unable to
assume the optimal inactive conformation needed
for Gleevac binding.
• Inhibitors with less stringent conformational
requirement for binding are predicted to retain
activity against mutant forms.
All material is derived from Shah et al. Science, 305, 399-401 (2004).