Novel, Selective CDK9 Inhibitors for the Treatment of HIV Infection

Abstract

Cyclin Dependent Kinases (CDKs) are important regulators of cell cycle and gene expression. Since an up-to-date review about the pharmacological inhibitors of CDK family (CDK1-10) is not available; therefore in the present paper we briefly summarize the most relevant inhibitors and point out the low number of selective inhibitors. Among CDKs, CDK9 is a validated pathological target in HIV infection, inflammation and cardiac hypertrophy; however selective CDK9 inhibitors are still not available. We present a selective inhibitor family of CDK9 based on the 4-phenylamino-6- phenylpyrimidine nucleus. We show a convenient synthetic method to prepare a useful intermediate and its derivatisation resulting in novel compounds. The CDK9 inhibitory activity of the derivatives was measured in specific kinase assay and the CDK inhibitory profile of the best ones (IC(50) < 100 nM) was determined. The most selective compounds had high selectivity over CDK1, 2, 3, 5, 6, 7 and showed at least one order of magnitude higher inhibitory activity over CDK4 inhibition. The most selective molecules were examined in cytotoxicity assays and their ability to inhibit HIV-1 replication was determined in cellular assays.

Synthesis, structure–activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents

“…Compound 9h (R 2 = CN, R 3 = m-SO 2 -morpholin-4-yl), with a bulkier morpholinosulfonamide at the meta-position of aniline, enhanced the selectivity for CDK9 over other CDKs when compared to 9e-g. Introduction of a methyl group at the paraposition while keeping the meta-morpholinosulfonamide resulted in compounds 9i-j, which showed a further improvement in selectivity for CDK9 over CDK1 and CDK2, however, the selectivity over CDK7 decreased dramatically. This is consistent with the SAR reported for another series of CDK9 inhibitors [26]. The C5-fluoro and C5-cyano substituted analogues were more potent than the corresponding C5-unsubstituted analogues, as evidenced by compounds 9j and 9i, 9m and 9l.…”

Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells

“…SNS-032 (BMS-387032) and flavopiridol were from Selleck Chemicals LLC and Sigma-Aldrich, respectively. The Cdk9 inhibitor VCC096179 was from Vinchem Chemie Research Ltd. and described as compound 87 in reference (28). The pancaspase inhibitor N-tert-butoxycarbonyl-Asp O-methylated-fluoromethyl ketone (Boc-D[OMe].fmk) was from Biovision.…”

“…We thank Dr. Eric Eldering (Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands) for NIH3T3 cells expressing CD154, Prof. Jannie Borst (Division of Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands) for anti-Bcl-A1 antibody, Paolo Cappella and Jurgen Moll (Nerviano Medical Sciences S.r.l.) for EdU-based replication assay protocol, Holger Stephan, Raffaella D'Auria, and Gemma O'Brien (NUIG) for Mcm2 antibodies, Maria Ryan (NUIG) for assistance with RT-qPCR, Joe Gooding (UCHG) for irradiating NIH3T3 cells and Gabor Nemeth (Vinchem Chemie Research Ltd.) for compound VCC096179 (28). We thank the personnel from UCHG and Galway Clinic for CD38 and interface FISH analysis and the patients who kindly provided samples.…”

Targeting HIV Transcription: The Quest for a Functional Cure

“…Finding a highly selective and non-cytotoxic CDK9 inhibitor is a difficult task due to its dual role in cellular and HIV transcription (Klebl and Choidas 2006; Nemeth et al 2011; Wang and Fischer 2008). Nevertheless, major efforts have been made to find small-molecule inhibitors targeting specifically the CDK9 activity and the function of P-TEFb complex in HIV replication.…”