title: Development of Alkyne-Containing Pyrazolopyrimidines To Overcome Drug Resistance of Bcr-Abl Kinase.
abstract: 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-Abl(T315I) 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 Abl(T315I) in vitro but also Bcr-Abl(T315I) in cells. These pyrazolopyrimidines can serve as lead compounds for future development of novel targeted therapy to overcome drug resistance of CML.
authors.affiliation: Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California , Los Angeles, California 90089, United States.
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California , Los Angeles, California 90089, United States.
authors.forename: Alvin
authors.initials: A
authors.lastname: Kung
authors.affiliation: Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California , Los Angeles, California 90089, United States.
authors.forename: Brock
authors.initials: B
authors.lastname: Malinoski
authors.affiliation: Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California , Los Angeles, California 90089, United States.
authors.forename: G K Surya
authors.initials: GK
authors.lastname: Prakash
authors.affiliation: Loker Hydrocarbon Research Institute & Department of Chemistry, University of Southern California , Los Angeles, California 90089, United States.|USC Norris Comprehensive Cancer Center, University of Southern California , Los Angeles, California 90089, United States.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
mesh_terms: D000480:Alkynes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000480:Alkynes; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016044:Fusion Proteins, bcr-abl