Pim kinase inhibitors in cancer: medicinal chemistry insights into their activity and selectivity

•Pim kinase proteins (pim-1/2/3) are potential chemotherapeutic targets in cancer.•Pim inhibition is currently the focus of intensive drug design and development efforts.•The unique presence of proline amino acid in hinge region spans the ability to inhibit pim kinases, while conserving other kinases’ physiological functions and reducing inhibitors’ toxicity profiles.•ATP-competitive pim inhibitors published in the period 2011-2020 have been reviewed.•The review focuses on structural features essential for high potency and selectivity. The oncogenic Pim kinase proteins (Pim-1/2/3) regulate tumorigenesis through phosphorylating essential proteins that control cell cycle and proliferation. Pim kinase is a potential chemotherapeutic target in cancer and its inhibition is currently the focus of intensive drug design and development efforts. The distinctive presence of proline amino acids in the hinge region provides an opportunity to inhibit Pim kinase while conserving the physiological functions of other kinases and reducing the toxicity profiles of the inhibitors. Various Pim kinase inhibitors have been clinically evaluated for the treatment of hematological cancers, yet none has reached the clinic. In this review, we discuss the design and development of selective and potent Pim inhibitors with novel chemotypes focusing on structural features essential for high potency and selectivity.