The CDK inhibitor AT7519M in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. A Phase II study of the Canadian Cancer Trials Group

Abstract

AT7519M is a small molecule inhibitor of cyclin-dependent kinases 1, 2, 4, 5, and 9 with in vitro activity against lymphoid malignancies. In two concurrent Phase II trials, we evaluated AT7519M in relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) using the recommended Phase II dosing of 27 mg/m twice weekly for 2 of every 3 weeks. Primary objective was objective response rate (ORR). Nineteen patients were accrued (7 CLL, 12 MCL). Four CLL patients achieved stable disease (SD). Two MCL patients achieved partial response (PR), and 6 had SD. One additional MCL patient with SD subsequently achieved PR 9 months after completion of AT7519M. Tumor lysis syndrome was not reported. In conclusion, AT7519M was safely administered to patients with relapsed/refractory CLL and MCL. In CLL, some patients had tumor reductions, but the ORR was low. In MCL, activity was noted with ORR of 27%.

In Vitro and In Vivo Antitumor and Anti-Inflammatory Capabilities of the Novel GSK3 and CDK9 Inhibitor ABC1183

“…AT7519 is a pan-CDK inhibitor that likewise caused G2/M arrest and decreased GSK3b ser9 phosphorylation. Multiple phase II clinical trials have been completed but, although treatment is well tolerated, low response rates were observed (Seftel et al, 2017). Therefore, ABC1183 represents a novel molecule for selectively inhibiting CDK9 and GSK3.…”

Pharmacophore-based virtual screening, synthesis, biological evaluation, and molecular docking study of novel pyrrolizines bearing urea/thiourea moieties with potential cytotoxicity and CDK inhibitory activities

“…However, compound 4 exhibited weaker inhibitory activity against CDK-2 (IC 50 ¼ 47 nM) compared to the parent compound 3 which indicates that the aromatic 4-fluorophenyl moiety is favoured for CDKs inhibition 16 , Figure 1. Mechanistic study of compound 4 also revealed high inhibitory activity against CDK-9, while weaker activity was observed against CDKs 1, 3, 4, and 6 17 . Moreover, replacement of the 4-piperidinyl ring in compound 4 by the N-4-((2aminophenyl)carbamoyl)benzyl moiety afforded compound 5 with higher inhibitory activities against CDK-1/2 18 .…”

“…Based on the above-mentioned data, the current study was performed to optimise the cytotoxic potential, study the structureactivity relationship (SAR), and investigate the mechanism of action of the pyrrolizine-5-carboxamide 10. In this study, scaffold A ( Figure 3) was designed bearing the pharmacophoric groups of the lead compound 10 and the multi-CDKIs 3 17 . In addition, a small library of 1302 urea/thiourea derivatives was generated through different structural modifications in scaffold A, Supplementary data ( Figures S1-S42).…”

“…Beside the cytotoxic activity, toxicity and selectivity towards normal cells are also critical factors in the discovery of new anticancer agents 56 . Accordingly, cytotoxicity of the new reported compounds (16)(17)(18)(19)(20) was also evaluated in the current study using the normal human foetal lung fibroblast (MRC-5). The investigation was performed using the MTT assay according to the previous reports 25 .…”

“…Our literature review [16][17][18] revealed several CDKIs bearing similar pharmacophoric groups which include two aryl/heterocyclic rings, two carbonyl groups, and a five-membered pyrazole/imidazole core, Figure 1. Among these inhibitors, compound 1 exhibited moderate inhibitory activity against CDK-2 with an IC 50 value of 0.324 lM 15 .…”