Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

Xie, Shao; Jiang, Hui; Zhai, Xiaowen; Fan, Wei; Wang, Shudong; Ding, Jian; Chen, Yi

doi:10.1038/aps.2016.49

Cited by 34 publications

(32 citation statements)

References 41 publications

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“…2A and B; Supplementary Tables S4-S6). Conversely, the other antiapoptotic BCL-2 and IAP family proteins were quite stable (BFL-1 and BCL-B were not detected) despite reports that XIAP was rapidly modulated upon CDK9 inhibition (28). Many other oncogenes, despite rapid mRNA turnover, either had prolonged protein half-lives or were not detected ( Supplementary Table S5).…”

Section: Cdk9 Inhibition By Azd4573 Results In Rapid Turnover Of Mcl-1mentioning

confidence: 98%

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

198

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: Cdk9 Inhibition By Azd4573 Results In Rapid Turnover Of Mcl-1mentioning

confidence: 98%

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

198

160

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“…To our knowledge, this particular drug pair has not been reported previously, however, this was not a novel mechanistic pairing as similar have been investigated by several other groups 33 – 35 . For example, Xie, et al 36 investigated LS-007, a CDK inhibitor, in combination with venetoclax against AML and observed a marked increase in apoptosis across a panel of AML cell lines. Additionally, several groups 37 , 38 have investigated the inhibition of CDK9 as a way of targeting AML blasts observing down-regulation of survival genes, including MCL1.…”

Section: Discussionmentioning

confidence: 99%

A compound combination screening approach with potential to identify new treatment options for paediatric acute myeloid leukaemia

Lappin

Davis

Matchett

et al. 2020

Sci Rep

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Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by genetics and morphology. The introduction of intensive chemotherapy treatments together with patient stratification and supportive therapy has resulted in a moderate improvement in patient prognosis. However, overall survival rates remain unacceptably poor, with only 65% of patients surviving longer than 5 years. Recently age-specific differences in AML have been identified, highlighting the need for tailored treatments for paediatric patients. Combination therapies have the potential to improve patient prognosis, while minimising harmful side-effects. In the laboratory setting, identifying key combinations from large drug libraries can be resource-intensive, prohibiting discovery and translation into the clinic. To minimise redundancy and maximise discovery, we undertook a multiplex screen of 80 apoptotic-inducing agents in paediatric AML pre-clinical models. The screen was designed using an all-pairs testing algorithm, which ensured that all pairs of compounds could be tested, while minimising the number of wells used. We identified a combination of ABT-737, a Bcl-2 family inhibitor and Purvalanol A, a CDK inhibitor, as a potential targeted therapy for AML patients with an MLL rearrangement and an FLT3-ITD. Our approach has the potential to reduce resource-intensity and time associated with the identification of novel combination therapies.

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“…For each of these CDK9 inhibitors, activity has been evaluated against various other CDK kinases [55][56][57][58][59]29,[60][61][62][63][64][65][66]. These selectivity profiles had been conveniently compiled into a recent review [22].…”

Section: Selectivity Of 14e and Of Other Cdk9 Inhibitorsmentioning

confidence: 99%

Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships

Kirubakaran

Morton

Zhang

et al. 2020

Preprint

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Cyclin-dependent kinase 9 (CDK9) plays a key role in transcription elongation, and more recently it was also identified as the molecular target of a series of diaminothiazole compounds that reverse epigenetic silencing in a phenotypic assay. To better understand the structural basis underlying these compounds' activity and selectivity, we developed a comparative modeling approach that we describe herein. Briefly, this approach draws upon the strong structural conservation across the active conformation of all protein kinases, and their shared pattern of interactions with Type I inhibitors.Because of this, we hypothesized that the large collection of inhibitor/kinase structures available in the Protein Data Bank (PDB) would enable accurate modeling of this diaminothiazole series in complex with each CDK family member. We apply this new comparative modeling pipeline to build each of these structural models, and then demonstrate that these models provide retrospective rationale for the structure-activity relationships that ultimately guided optimization to the lead diaminothiazole compound MC180295 (14e). We then solved the crystal structure of the 14e/CDK9 complex, and found the resulting structure to be in excellent agreement with our corresponding comparative model. Finally, inspired by these models, we demonstrate how structural changes to 14e can be used to rationally tune this compound's selectivity profile. With the emergence of CDK9 as a promising target for therapeutic intervention in cancer, we anticipate that comparative modeling can provide a valuable tool to guide optimization of potency and selectivity of new inhibitors targeting this kinase.anti-tumoral activity coupled with immunosensitization [28]. With respect to selectivity, the preference of 14e for CDK9 over CDK2 and CDK7 was especially notable: due to their structural and functional similarities, most CDK9 inhibitors also inhibit CDK2 and CDK7 [29,30]. In our first study, we explored selectivity of 14e by developing a comparative modeling approach to build a model of the 14e/CDK9 complex, and then using this model to propose a structural basis for the observed selectivity [28].In the present study we expand our understanding of the structure-activity relationship (SAR) of the series and use these data to critically evaluate our comparative modeling approach. In particular, we present the SAR of 77 compounds related to 14e, and retrospectively assess the extent to which comparative modeling could have driven optimization. We also characterize 14e selectivity further, in light of a recent study demonstrating the surprising lack of selectivity in compounds ostensibly selective for other CDKs [6], and a report summarizing the broad selectivity profiles of CDK9 inhibitors that have advanced to clinical trials [22]. Finally, to definitively evaluate the accuracy of our comparative modeling for this application, we solve the crystal structure of 14e in complex with CDK9. Results and DiscussionOur previous study culminated with the identification and c...

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Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells

Cited by 34 publications

References 41 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 compound combination screening approach with potential to identify new treatment options for paediatric acute myeloid leukaemia

Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships

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