Molecular hybrids: A five-year survey on structures of multiple targeted hybrids of protein kinase inhibitors for cancer therapy

Protein kinases have grown over the past few years as a crucial target for different cancer types. With the multifactorial nature of cancer, and the fast development of drug resistance for conventional chemotherapeutics, a strategy for designing multi-target agents was suggested to potentially increase drug efficacy, minimize side effects and retain the proper pharmacokinetic properties. Kinase inhibitors were used extensively in such strategy. Different kinase inhibitor agents which target EGFR, VEGFR, c-Met, CDK, PDK and other targets were merged into hybrids with conventional chemotherapeutics such as tubulin polymerization and topoisomerase inhibitors. Other hybrids were designed gathering kinase inhibitors with targeted cancer therapy such as HDAC, PARP, HSP 90 inhibitors. Nitric oxide donor molecules were also merged with kinase inhibitors for cancer therapy. The current review presents the hybrids designed in the past five years discussing their design principles, results and highlights their future perspectives. [Display omitted] •Molecular hybridization is a promising drug design strategy used for cancer therapy.•Kinase inhibitors are merged with other chemotherapeutic agents to create a hybrid.•Decreased drug resistance, reduced drug interactions, high efficiency are benefits.•Side effects prediction and pharmacokinetics control is complicated.