Turning promiscuous kinase inhibitors into safer drugs.
Burgeoning interest in multi-target drugs to treat complex diseases and malignancies has motivated a reassessment of the therapeutic value of promiscuity. Although drug efficacy might not correlate with specificity, it would be risky to welcome promiscuous compounds without a rational strategy to control therapeutic impact. This situation might change as novel selectivity filters are incorporated into drug design. For example, cardiotoxic side effects of the cancer drug imatinib might be curbed by applying such premises. Here, we survey approaches to control the therapeutic impact of cross-reactive kinase inhibitors and advocate the application of a novel selectivity filter by illustrating its cleaning efficacy. Finally, we evaluate the possibility of turning multi-target kinase inhibitors into clinical opportunities through judicious chemical modifications.
Zhang
Xi
X
Program in Applied Physics, Rice Quantum Institute, Rice University, 6100 Main St, Houston, TX 77005, USA.
Crespo
Alejandro
A
Fernández
Ariel
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D001549:Benzamides; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D008968:Molecular Conformation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000138:chemical synthesis; D011743:Pyrimidines / Q000138:chemical synthesis; D013379:Substrate Specificity; D013678:Technology, Pharmaceutical / Q000379:methods
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D010770:Phosphotransferases