Abstract 3572: AZ5576, a novel potent and selective CDK9 inhibitor, induces rapid cell death and achieves efficacy in multiple preclinical hematological models

Deregulation of the MYC transcription factor is a key driver in lymphomagenesis. MYC induces global changes in gene expression that contribute to cell growth, proliferation, and oncogenesis by stimulating the activity of RNA polymerases. A key feature in its ability to stimulate RNA Pol II activity is recruitment of pTEFb, an elongation factor whose catalytic core comprises CDK9/cyclin T complexes. Hence, MYC expression and function may be susceptible to CDK9 inhibition. We conducted a pre-clinical assessment of AZ5576, a selective CDK9 inhibitor, in diffuse large B-cell lymphoma (DLBCL). The in vitro and in vivo effects of AZ5576 on apoptosis, cell cycle, Mcl-1, and MYC expression were assessed by flow cytometry, immunoblotting, qPCR and RNA-Seq. We demonstrate that, in addition to depleting Mcl-1, targeting CDK9 disrupts MYC oncogenic function.Treatment with AZ5576 inhibited growth of DLBCL cell lines in vitro and in vivo, independent of cell-of-origin. CDK9 inhibition downregulated Mcl-1 and MYC mRNA transcript and protein in a dose-dependent manner. MYC-expressing cell lines demonstrated enhanced susceptibility to AZ5576. CDK9 inhibition promoted turnover of MYC protein, and decreased MYC phosphorylation at the stabilizing Ser62 residue and downregulated MYC transcriptional targets in DLBCL cells, a finding confirmed in a functional reporter assay, suggesting that CDK9 may govern MYC protein turnover, thus regulating its expression through multiple mechanisms. Our data suggest that targeting CDK9 is poised to disrupt MYC oncogenic activity in DLBCL and provide rationale for clinical development of selective CDK9 inhibitors.

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“…S5; ref. 13). Thus, selective targeting of CDK9 induces apoptosis of DLBCL cells independent of COO in vitro and in vivo.…”

Section: Selective Targeting Of Cdk9 Restricts Growth Of Dlbcl Cells Independent Of Cell-of-originmentioning

confidence: 99%

Cyclin-Dependent Kinase-9 Is a Therapeutic Target in MYC-Expressing Diffuse Large B-Cell Lymphoma

Hashiguchi

Bruss

Best

et al. 2019

Molecular Cancer Therapeutics

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“…31 More selective CDK9 inhibitors have since emerged. We 32 and others 33 reported the characterization of the in vitro and in vivo CDK9 pharmacology using a preclinical tool 2 (AZ5576) identified as a reasonably potent and highly selective CDK9 inhibitor from a series of amidopyridines. 34 In vitro treatment of the acute myeloid leukemia (AML) cell line MV-4-11 with 2 resulted in a dose-and time-dependent decrease in pSer2-RNAP2 and Mcl-1 expression with subsequent activation of caspase 3/7, leading to rapid induction of cell death.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies

et al. 2020

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A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose-and timedependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.

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“…12,13 Pharmaceutical Fronts Vol. obtain the intermediate tert-butyl ((1R,4r)-4-(((R)-1methoxypropan-2-yl)amino)cyclohexyl)carbamate (10). Intermediate 10 was quickly reacted with hydrochloric acid solution to deprotect the Boc group, and gave (1r,4R)-N 1 -((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine (11) hydrochloride salt.…”

Section: Optimized Synthetic Routementioning

confidence: 99%

“…[1][2][3][4][5] Many CDK9 inhibitors have been developed or are currently being in various stages of clinical development for cancer treatment. [6][7][8][9][10] NVP-2 (1), chemical name "4-(((5′-chloro-2'-(((1R,4r)-4-(((R)-1methoxypropan-2-yl)amino)cyclohexyl)amino)-[2,4'-bipyridin]-6-yl)amino)methyl)tetrahydro-2H-pyran-4-carbonitrile," is a novel selective ATP-competitive CDK9 inhibitor developed by Novartis in 2011. NVP-2 displays a very potent CDK9/CycT inhibitory activity with an IC 50 value of 0.51 nmol/L, and more than 1,000-fold selectivity over CDK1/ CycB, CDK2/CycA, and CDK16/CycY.…”

Section: Introductionmentioning

confidence: 99%

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Efficient Synthesis and Docking Analysis of Selective CDK9 Inhibitor NVP-2

Saidahmatov

Liang

Shi

et al. 2021

Pharmaceutical Fronts

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Graphical AbstractNVP-2 (1), a potent and selective inhibitor of cyclin-dependent kinase 9 (CDK9), showed potent antitumor activity in preclinical studies. In this work, we designed and adopted a convergent synthetic route to efficiently synthesize NVP-2 (1). The key intermediate (7) was synthesized from malononitrile (2) and 1-bromo-2-(2-bromoethoxy)ethane (3) by successive cyclization, reduction, nucleophilic substitution with 2-bromo-6-fluoropyridine, and Suzuki–Miyaura reaction with (5-chloro-2-fluoropyridin-4-yl)boronic acid. Another key intermediate (11) was synthesized from (S)-1-methoxypropan-2-ol (8) by reaction with TsCl, electrophilic substitution reaction with tert-butyl ((1r,4r)-4-aminocyclohexyl)carbamate, and then by deprotection of Boc. Finally, a substitution reaction by the key intermediates (7) and (11) to afford the target product NVP-2 (1). The reaction conditions of the whole synthesis process were simple and mild, free of harsh conditions such as the microwave reaction and dangerous reagents in the original patent, and realized the efficient synthesis of NVP-2. In addition, we analyzed the binding mode of NVP-2 in the active pocket of CDK9 to provide reasonable design ideas for subsequent discovery of novel CDK9 inhibitors.

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Abstract 3572: AZ5576, a novel potent and selective CDK9 inhibitor, induces rapid cell death and achieves efficacy in multiple preclinical hematological models

Cited by 7 publications

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Cyclin-Dependent Kinase-9 Is a Therapeutic Target in MYC-Expressing Diffuse Large B-Cell Lymphoma

Cyclin-Dependent Kinase-9 Is a Therapeutic Target in MYC-Expressing Diffuse Large B-Cell Lymphoma

Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies

Efficient Synthesis and Docking Analysis of Selective CDK9 Inhibitor NVP-2

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