Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition

Dey, Joyoti; Deckwerth, Thomas L.; Kerwin, William S.; Casalini, Joseph; Merrell, Angela; Grenley, Marc; Burns, Connor; Ditzler, Sally; Dixon, Chantel; Beirne, Emily; Gillespie, Kate C.; Kleinman, Edward F.; Klinghoffer, Richard A.

doi:10.1038/s41598-017-18368-w

Cited by 79 publications

(64 citation statements)

References 47 publications

(62 reference statements)

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“…There are various studies that have successfully associated CDK9 inhibition with MCL-1 depletion and subsequent induction of tumor cell death (41). However, many come with study design caveats such as prolonged CDK9 inhibition (15,42), a narrow focus on one indication and/or a limited number of preclinical models (8,43), and use of nonselective compounds (14,44) that make it difficult to draw firm conclusions. This study overcame those limitations by utilizing the selective CDK9 inhibitor, AZD4573, and applying multiple approaches to interrogate the mechanism of action of CDK9 inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Despite clinical development of multiple inhibitors with CDK9 activity, the precise mode of action driving antitumor effects has yet to be fully elucidated, although their preclinical activity has been attributed predominantly to depletion of MCL-1 protein and subsequent induction of tumor cell death (13)(14)(15). MCL-1 is an antiapoptotic, BCL-2 family protein whose high expression has been associated with increased cancer cell survival that translates to chemotherapy resistance and poor patient prognosis (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

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AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

Cidado

Boiko

Proia

et al. 2020

Clinical Cancer Research

185

160

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Purpose: Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and potential therapeutic target for many cancers. Multiple nonselective CDK9 inhibitors have progressed clinically but were limited by a narrow therapeutic window. This work describes a novel, potent, and highly selective CDK9 inhibitor, AZD4573. Experimental Design: The antitumor activity of AZD4573 was determined across broad cancer cell line panels in vitro as well as cell line-and patient-derived xenograft models in vivo. Multiple approaches, including integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacologic comparisons, were employed to further understand the major mechanism driving AZD4573 activity and to establish an exposure/ effect relationship. Results: AZD4573 is a highly selective and potent CDK9 inhibitor. It demonstrated rapid induction of apoptosis and subsequent cell death broadly across hematologic cancer models in vitro, and MCL-1 depletion in a dose-and time-dependent manner was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. This pharmacodynamic (PD) response was also observed in vivo, which led to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses both as monotherapy or in combination with venetoclax. This understanding of the mechanism, exposure, and antitumor activity of AZD4573 facilitated development of a robust pharmacokinetic/PD/efficacy model used to inform the clinical trial design. Conclusions: Selective targeting of CDK9 enables the indirect inhibition of MCL-1, providing a therapeutic option for MCL-1dependent diseases. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematologic malignancies (clinicaltrials.gov identifier: NCT03263637). See related commentary by Alcon et al., p. 761

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

Cidado

Boiko

Proia

et al. 2020

Clinical Cancer Research

185

160

View full text Add to dashboard Cite

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“…The consequence of this promiscuity has been elegantly demonstrated in T98G glioblastoma cells, where introduction of a kinase-dead, dominant-negative mutant CDK9 results in a gene expression profile that is distinct from that induced by flavopiridol [26]. While the latter study emphasizes the polypharmacology of flavopiridol, identifying precise targets associated with clinical toxicity has been challenging [27]. In addition, the pharmacokinetic properties of flavopiridol and other inhibitors such as dinaciclib require intravenous dosing, with different infusion schedules being explored in specific trials [4,5,7,[28][29][30].…”

Section: Introductionmentioning

confidence: 99%

A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies

et al. 2019

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MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. Synergistic cell killing was also observed between A-1592668 or the related analog A-1467729, and venetoclax in a number of hematologic cell lines and primary NHL patient samples. Importantly, the CDK9 inhibitor plus venetoclax combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in mouse models of lymphoma and AML. These data indicate that CDK9 inhibitors could be highly efficacious in tumors that depend on MCL-1 for survival or when used in combination with venetoclax in malignancies dependent on MCL-1 and BCL-2.

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“…Although they appeared to share a similar mechanism of action in vitro, CDKI-73 has an advantage of better pharmacokinetics and higher oral bioavailability than flavopiridol. Moreover, the dose-limiting toxicity due to lack of selectivity and prolonged CDK9 inhibition narrowed the therapeutic index of flavopiridol (Dey et al, 2017;Lanasa et al, 2015), whereas CDKI-73 has shown a remarkably reduction of toxicity in non-cancerous cells . Western blot analysis of the tumours collected from xenografted mice treated with CDKI-73 confirmed its inhibition of CDK9 in vivo (Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting CDK9 for treatment of colorectal cancer

et al. 2019

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Colorectal cancer (CRC) remains one of the most lethal human malignancies, and pursuit of new therapeutic targets for treatment has been a major research focus. Cyclin‐dependent kinase 9 (CDK9), which plays a crucial role in transcription, has emerged as a target for cancer treatment. CDKI‐73, one of the most potent and pharmacologically superior CDK9 inhibitors, has demonstrated excellent anti‐tumour efficacy against several types of cancers. In this study, we evaluated its therapeutic potential against CRC. CDKI‐73 elicited high cytotoxicity against all colon cancer cell lines tested. Cell cycle and apoptosis analysis in HCT 116 and HT29 cells revealed that CDKI‐73 induced cell death without accumulation of DNA at any phase of the cell cycle. Moreover, it caused depolarisation of mitochondrial membrane, leading to caspase‐independent apoptosis. Knockdown by shRNA demonstrated the CDK9‐targeted mechanism of CDKI‐73, which also affected the Mnk/eIF4E signalling axis. In addition, RT‐qPCR analysis showed that CDKI‐73 down‐regulated multiple pro‐survival factors at the mRNA level. Its in vivo anti‐tumour efficacy was further evaluated in Balb/c nude mice bearing HCT 116 xenograft tumours. CDKI‐73 significantly inhibited tumour growth (***P < 0.001) without overt toxicity. Analysis of the tumour tissues collected from the xenografted animals confirmed that the in vivo anti‐tumour efficacy was associated with CDK9 targeting of CDKI‐73. Overall, this study provides compelling evidence that CDKI‐73 is a promising drug candidate for treating colorectal cancer.

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Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition

Cited by 79 publications

References 47 publications

AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells

A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies

Targeting CDK9 for treatment of colorectal cancer

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