ArticleBritish journal of cancer2013
Development of a cyclin-dependent kinase inhibitor devoid of ABC transporter-dependent drug resistance.
Article in British journal of cancer, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- Eco-friendly synthesis of novel pyrazole derivatives and their anticancer and CDK2 inhibitory activities.RSC advances · 2025Article
- Exploring isoindolin-1-ones as potential CDK7 inhibitors using cheminformatic tools.In silico pharmacology · 2024Article
- CDK7 inhibitors as anticancer drugs.Cancer metastasis reviews · 2020Review
- ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.Oncogene · 2020Article
- EI24 Inhibits Cell Proliferation and Drug Resistance of Esophageal Squamous Cell Carcinoma.Frontiers in oncology · 2020Article
- Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma.British journal of cancer · 2019Article
- CAC1 knockdown reverses drug resistance through the downregulation of P-gp and MRP-1 expression in colorectal cancer.PloS one · 2019Article
- The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death.British journal of cancer · 2018Article
- Targeting bromodomain and extraterminal proteins in breast cancer.Pharmacological research · 2018Review
- AKT activation controls cell survival in response to HDAC6 inhibition.Cell death & disease · 2016Article
- Selective CDK7 inhibition with BS-181 suppresses cell proliferation and induces cell cycle arrest and apoptosis in gastric cancer.Drug design, development and therapy · 2016Article
- CDK/CCN and CDKI alterations for cancer prognosis and therapeutic predictivity.BioMed research international · 2014Review
- Article
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundCyclin-dependent kinases (CDKs) control cell cycle progression, RNA transcription and apoptosis, making them attractive targets for anticancer drug development. Unfortunately, CDK inhibitors developed to date have demonstrated variable efficacy.
methodsWe generated drug-resistant cells by continuous low-dose exposure to a model pyrazolo[1,5-a]pyrimidine CDK inhibitor and investigated potential structural alterations for optimal efficacy.
resultsWe identified induction of the ATP-binding cassette (ABC) transporters, ABCB1 and ABCG2, in resistant cells. Assessment of features involved in the ABC transporter substrate specificity from a compound library revealed high polar surface area (>100 Å(2)) as a key determinant of transporter interaction. We developed ICEC-0782 that preferentially inhibited CDK2, CDK7 and CDK9 in the nanomolar range. The compound inhibited phosphorylation of CDK substrates and downregulated the short-lived proteins, Mcl-1 and cyclin D1. ICEC-0782 induced G2/M arrest and apoptosis. The permeability and cytotoxicity of ICEC-0782 were unaffected by ABC transporter expression. Following daily oral dosing, the compound inhibited growth of human colon HCT-116 and human breast MCF7 tumour xenografts in vivo by 84% and 94%, respectively.
conclusionWe identified a promising pyrazolo[1,5-a]pyrimidine compound devoid of ABC transporter interaction, highly suitable for further preclinical and clinical evaluation for the treatment of cancer.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.