CDK9 inhibitors in acute myeloid leukemia

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Current treatment for acute myeloid leukemia (AML) is less than optimal, but increased understanding of disease pathobiology and genomics has led to clinical investigation of novel targeted therapies and rational combinations. Targeting the cyclin-dependent kinase 9 (CDK9) pathway, which is dysregulated in AML, is an attractive approach. Inhibition of CDK9 leads to downregulation of cell survival genes regulated by super enhancers such as MCL-1, MYC, and cyclin D1. As CDK9 inhibitors are nonselective, predictive biomarkers that may help identify patients most likely to respond to CDK9 inhibitors are now being utilized, with the goal of improving efficacy and safety.

Electronic supplementary material

The online version of this article (10.1186/s13046-018-0704-8) contains supplementary material, which is available to authorized users.

Related collections

Most cited references 84

Record: found
Abstract: found
Article: not found

A quantitative analysis of kinase inhibitor selectivity.

Anne M. Floyd, Edward W. Chan, Patrick P Zarrinkar … (2007)

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

0 comments Cited 187 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Mammalian cyclin-dependent kinases.

Mariano Barbacid, Marcos Malumbres (2005)

Cyclin-dependent kinases (Cdks) are the catalytic subunits of a family of mammalian heterodimeric serine/threonine kinases that have been implicated in the control of cell-cycle progression, transcription and neuronal function. Recent genetic evidence obtained with gene-targeted mice has shown that Cdk4 and Cdk6 are not needed for entry into the cell cycle after mitogenic stimuli and organogenesis; however, they are essential for the proliferation of some endocrine and hematopoietic cells. Cdk2 is also dispensable for the mitotic cell cycle. Indeed, mice without Cdk2 are normal except for their complete sterility: unexpectedly, Cdk2 is crucial for the first meiotic division of male and female germ cells. These findings have important implications both for our current understanding of the role of Cdks in regulating the mammalian cell cycle and for their potential use as therapeutic targets in cancer.

0 comments Cited 107 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor.

Jamie P. Dwyer, Thierry Fischmann, Deepa Prabhavalkar … (2010)

Cyclin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets in oncology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC(50) values of 1, 1, 3, and 4 nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. (c) 2010 AACR.

0 comments Cited 91 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Silvia Boffo: tue91800@temple.edu

Angela Damato: angeladamato1985@gmail.com

Luigi Alfano: l.alfano@istitutotumori.na.it

Antonio Giordano: giordano@temple.edu

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 23 February 2018

Publication date PMC-release: 23 February 2018

Publication date Collection: 2018

Volume: 37

Electronic Location Identifier: 36

Affiliations

[1 ]ISNI 0000 0001 2248 3398, GRID grid.264727.2, Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, , Temple University, ; 1900 N. 12th St., Room 431, Philadelphia, PA 19122-6017 USA

[2 ]Medical Oncology Unit, Clinical Cancer Centre, IRCCS–Arcispedale S. Maria Nuova, Reggio Emilia, Italy

[3 ]ISNI 0000 0004 1763 1319, GRID grid.482882.c, Oncology Research Center of Mercogliano (CROM), Istituto Nazionale Per Lo Studio E La Cura Dei Tumori “Fondazione Giovanni Pascale”, , IRCCS, ; Naples, Italy

[4 ]ISNI 0000 0004 1757 4641, GRID grid.9024.f, Department of Medicine, Surgery, and Neuroscience, , University of Siena, ; Siena, Italy

Article

Publisher ID: 704

DOI: 10.1186/s13046-018-0704-8

PMC ID: 5824552

PubMed ID: 29471852

SO-VID: ac84fc2c-d7ba-468a-aae1-1829dd7eb8bc

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 11 November 2017

Date accepted : 12 February 2018

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acute myeloid leukemia,cdk9 inhibitor,positive transcription elongation factor b,p-tefb,mcl-1,myc

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: acute myeloid leukemia, cdk9 inhibitor, positive transcription elongation factor b, p-tefb, mcl-1, myc

CDK9 inhibitors in acute myeloid leukemia

Read this article at

Abstract

Electronic supplementary material

Related collections

Karger: Oncology

Most cited references 84

A quantitative analysis of kinase inhibitor selectivity.

Mammalian cyclin-dependent kinases.

Dinaciclib (SCH 727965), a novel and potent cyclin-dependent kinase inhibitor.

Author and article information

Contributors

Journal

Affiliations

Article

History

Categories

Custom metadata

Comments

Comment on this article

Similar content 647

Cited by 58

Most referenced authors 1,766