Development of Alkyne-Containing Pyrazolopyrimidines To Overcome Drug Resistance of Bcr-Abl Kinase

Despite
the success of imatinib at inhibiting Bcr-Abl and treating
chronic myelogenous leukemia (CML), resistance to the therapy occurs
over time in patients. In particular, the resistance to imatinib caused
by the gatekeeper mutation T315I in Bcr-Abl remains a challenge in
the clinic. Inspired by the successful development of ponatinib to
curb drug resistance, we hypothesize that the incorporation of an
alkyne linker in other heterocyclic scaffolds can also achieve potent
inhibition of Bcr-AblT315I by allowing for simultaneous
occupancy of both the active site and the allosteric pocket in the
Abl kinase domain. Herein, we describe the design, synthesis, and
characterization of a series of alkyne-containing pyrazolopyrimidines
as Bcr-Abl inhibitors. Our results demonstrate that some alkyne-containing
pyrazolopyrimidines potently inhibit not only AblT315I in
vitro but also Bcr-AblT315I in cells. These pyrazolopyrimidines
can serve as lead compounds for future development of novel targeted
therapy to overcome drug resistance of CML.