Discovery of Dual CDK6/PIM1 Inhibitors with a Novel Structure, High Potency, and Favorable Druggability for the Treatment of Acute Myeloid Leukemia

Abstract

Nowadays, the simultaneous inhibition of two or more pathways plays an increasingly important role in cancer treatment due to the complex and diverse pathogenesis of cancer, and the combination of the cyclin-dependent kinase 6 (CDK6) inhibitor and PIM1 inhibitor was found to generate synergistic effects in acute myeloid leukemia (AML) treatment. Therefore, we discovered a novel lead 1 targeting CDK6/PIM1 via pharmacophore-based and structure-based virtual screening, synthesized five different series of new derivates, and obtained a potent and balanced dual CDK6/PIM1 inhibitor 51, which showed high kinase selectivity. Meanwhile, 51 displayed an excellent safety profile and great pharmacokinetic properties. Furthermore, 51 displayed stronger potency in reducing the burden of AML than palbociclib and SMI-4a in vivo. In summary, we offered a new direction for AML treatment and provided a great lead compound for AML preclinical studies.Article pubs.acs.org/jmc

Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

“…Meanwhile, the pyrimidine ring formed many π−alkyl interactions with CDK6. Based on the binding model of 8 with CDK6 and previous literatures, 15,25,26 pyridine. When the substituent group on the piperazine ring was changed to isopropyl (16, Table 2), the CDK6 inhibitory activity was not significantly improved.…”

“…24 was obtained through the reaction of M17b and M3a by the same synthetic method of 8, yield 43%. 1 [1,4]dioxin-6-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-3-yl) (4-isopropylpiperazin-1-yl)methanone (25). 25 was obtained through the reaction of M17b and M3b by the same synthetic method of 8, yield 38%.…”

Stereoselective synthesis of 3,4‐dihydropyrrolo[1,2‐a]pyrazin‐1(2H)‐one derivatives as PIM kinase inhibitors inspired from marine alkaloids

“…Accordingly, simultaneous inhibition of PIM and PI3K kinases could have a clinical benefit 9–12 . Similarly, synergistic effect of PIM1 and cyclin‐dependent kinase 6 (CDK6) inhibition in AML was also reported 13 …”

“…[9][10][11][12] Similarly, synergistic effect of PIM1 and cyclin-dependent kinase 6 (CDK6) inhibition in AML was also reported. 13 Several PIM inhibitors have been developed; among them, the pan-PIM inhibitors PIM447, 14 INCB053914, and TP-3654 are currently in clinical trials. [15][16][17] Heterocyclic compounds containing the 3,4-dihydropyrrolo [1,2-a]pyrazin-1(2H)-one moiety occur in a number of natural products of marine origin.…”

Synthesis of Morpholine-, Piperidine-, and N-Substituted Piperazine-Coupled 2-(Benzimidazol-2-yl)-3-arylquinoxalines as Novel Potent Antitumor Agents

“…The most promising compounds for oncological practice inhibit tumor growth, which is associated with their ability to bind DNA, and structures such as substituted bicyclic systems with piperazine, piperidine, and morpholine fragments on the one hand and various heterocyclic fragments on the other with a common C–N bond (Figure , structures of type A ) ,− carbo- and hetarylquinoxalines (Figure , structures of type B and C ), − and heteroarylbenzimidazoles (Figure , structures of type D ) − with a common C–C bond, including benzimidazolylquinoxalines , with various substituents, exhibit pronounced antitumor activity. From all the above-mentioned thought this prompted us to obtain new regioisomeric derivatives of 2-(benzimidazol-2-yl)-3-arylquinoxalines with piperazine, piperidine, and morpholine fragments at positions 6 and 7 (Figure , structures 13/14 : X = NMe, NPh, CH 2 , O) for a detailed study of their interaction with DNA and antitumor activity on a panel of cancer cell lines.…”