PXD013796

PXD013796 is an original dataset announced via ProteomeXchange.

Title	AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells
Description	Phosphorylation of RNA polymerase II by cyclin-dependent kinase 9 (CDK9) is crucial for transcriptional regulation, and acute inhibition of CDK9 results in the rapid downregulation of genes with short-lived transcripts and labile proteins. Multiple non-selective 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. Using integrated transcriptomic and proteomic analyses, loss-of-function pathway interrogation, and pharmacological comparisons, Mcl-1 depletion was identified as a major mechanism through which AZD4573 induces cell death in tumor cells. AZD4573 suppresses Mcl-1 in a dose- and time-dependent manner that causes caspase-3 cleavage in sensitive cancer cells, most notably in hematological malignancies. This pharmacodynamic response is observed in vivo as well, which leads to regressions in both subcutaneous tumor xenografts and disseminated models at tolerated doses as monotherapy or in combination with venetoclax. Fully understanding the mechanism, exposure, and anti-tumor activity of AZD4573 also informed the development of a robust PK/PD/efficacy model that helped select and predict the starting and efficacious dose range in man. Accordingly, AZD4573 is currently being evaluated in a phase I clinical trial for patients with hematological malignancies (clinicaltrials.gov identifier: NCT03263637).
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:04:25.327.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Valar Nila Roamio Franklin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	methylthiolated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-10 06:19:40	ID requested
1	2020-05-26 05:26:35	announced
⏵ 2	2024-10-22 05:04:28	announced	2024-10-22: Updated project metadata.

Cidado J, Boiko S, Proia T, Ferguson D, Criscione SW, San Martin M, Pop-Damkov P, Su N, Roamio Franklin VN, Sekhar Reddy Chilamakuri C, D'Santos CS, Shao W, Saeh JC, Koch R, Weinstock DM, Zinda M, Fawell SE, Drew L, AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer Cells. Clin Cancer Res, 26(4):922-934(2020) [pubmed]

10.1158/1078-0432.ccr-19-1853;

submitter keyword: a selective CDK9 inhibitor,AZD4573, targets Mcl-1

Clive D'Santos
contact affiliation	Cambridge University
contact email	clivesdsantos@gmail.com
lab head
Valar Nila Roamio Franklin
contact affiliation	Research Assistant
contact email	Valar.Franklin@cruk.cam.ac.uk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2020/05/PXD013796

PRIDE project URI

• PRIDE
  1. PXD013796
     1. Label: PRIDE project
     2. Name: AZD4573 is a highly selective CDK9 inhibitor that suppresses Mcl-1 and induces apoptosis in hematological cancer cells