Multiomics Profiling Establishes the Polypharmacology of FDA-Approved CDK4/6 Inhibitors and the Potential for Differential Clinical Activity.
CDK4/6 inhibitors
abemaciclib
breast cancer
cancer therapeutics
drug mechanisms of action
drug profiling
kinase inhibitors
palbociclib
ribociclib
Journal
Cell chemical biology
ISSN: 2451-9448
Titre abrégé: Cell Chem Biol
Pays: United States
ID NLM: 101676030
Informations de publication
Date de publication:
15 08 2019
15 08 2019
Historique:
received:
12
11
2018
revised:
14
03
2019
accepted:
13
05
2019
pubmed:
11
6
2019
medline:
22
10
2020
entrez:
11
6
2019
Statut:
ppublish
Résumé
The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6-collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic, and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/cyclin A/E-implicated in resistance to CDK4/6 inhibition-and CDK1/cyclin B. The multifaceted experimental and computational approaches described here therefore uncover underappreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.
Identifiants
pubmed: 31178407
pii: S2451-9456(19)30174-6
doi: 10.1016/j.chembiol.2019.05.005
pmc: PMC6936329
mid: NIHMS1058487
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
CDK4 protein, human
EC 2.7.11.22
CDK6 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinase 4
EC 2.7.11.22
Cyclin-Dependent Kinase 6
EC 2.7.11.22
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1067-1080.e8Subventions
Organisme : NIGMS NIH HHS
ID : P50 GM107618
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA225088
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL127365
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.
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