Utilization of cyanopyridine in design and synthesis of first-in-class anticancer dual acting PIM-1 kinase/HDAC inhibitors.

Herein, we report design and synthesis of twenty-one dual PIM-1/HDAC inhibitors utilizing 3-cyanopyridines as a novel cap moiety linked with aliphatic /aromatic linker bearing carboxylic acid 3a-g, hydroxamic acid 4a-g or 2-aminoanilide moieties 5a-g as zinc-binding group. Most of the target hybrids revealed promising growth inhibition according to one dose NCI protocol against 60 cancer cell lines. Meanwhile, hydroxamic acids 4b, 4d and 4e displayed strong and broad-spectrum activity against nine tumor subpanels tested (GI50 0.176-8.87 µM); 4d displayed strong antiproliferative activity with GI50 ≤ 3 µM against different cancer cell lines (GI50 range from 0.325 to 2.9 µM). Furthermore, 4a, 4d-4g and 5f manifested a high inhibitory activity against HDACs 1 and 6 isozymes; 4g, displayed potent HDAC 1 and 6 inhibitory activity (45.01 ± 2.1 and 19.78 ± 1.1 nM) more than the reference SAHA (51.54 ± 2.4 and 21.38 ± 1.2 nM, respectively), while 4f was more potent (30.09 ± 1.4 nM) than SAHA against HDAC 1 and less potent (30.29 ± 1.7 nM) than SAHA against HDAC 6. Hybrids 4b, 4d, 4e and 4f exhibited potent PIM-1 inhibitory activity; 4d showed comparable activity to quercetin (IC50 of 343.87 ± 16.6 and 353.76 ± 17.1 nM, respectively); it exhibited pre G1 apoptosis and arrest cell cycle at G2/M phase. Moreover, it revealed good binding into pocket of HDACs 1,6 and PIM-1 kinase enzymes with good correlation with biological results. Moreover, 4b, 4d and 4e had reasonable drug-likeness properties according to Lipinski's rule. However, multitarget inhibitor of PIM-1/HDAC is a promising strategy in anticancer drug discovery; the most potent hybrids require further in vivo and clinical investigations.

Comprehensive review for anticancer hybridized multitargeting HDAC inhibitors.

Despite the encouraging clinical progress of chemotherapeutic agents in cancer treatment, innovation and development of new effective anticancer candidates still represents a challenging endeavor. With 15 million death every year in 2030 according to the estimates, cancer has increased rising of an alarm as a real crisis for public health and health systems worldwide. Therefore, scientist began to introduce innovative solutions to control the cancer global health problem. One of the promising strategies in this issue is the multitarget or smart hybrids having two or more pharmacophores targeting cancer. These rationalized hybrid molecules have gained great interests in cancer treatment as they are capable to simultaneously inhibit more than cancer pathway or target without drug-drug interactions and with less side effects. A prime important example of these hybrids, the HDAC hybrid inhibitors or referred as multitargeting HDAC inhibitors. The ability of HDAC inhibitors to synergistically improve the efficacy of other anti-cancer drugs and moreover, the ease of HDAC inhibitors cap group modification prompt many medicinal chemists to innovate and develop new generation of HDAC hybrid inhibitors. Notably, and during this short period, there are four HDAC inhibitor hybrids have entered different phases of clinical trials for treatment of different types of blood and solid tumors, namely; CUDC-101, CUDC-907, Tinostamustine, and Domatinostat. This review shed light on the most recent hybrids of HDACIs with one or more other cancer target pharmacophore. The designed multitarget hybrids include topoisomerase inhibitors, kinase inhibitors, nitric oxide releasers, antiandrogens, FLT3 and JAC-2 inhibitors, PDE5-inhibitors, NAMPT-inhibitors, Protease inhibitors, BRD4-inhibitors and other targets. This review may help researchers in development and discovery of new horizons in cancer treatment.