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J Med Chem. 2018 Feb 22;61(4):1664-1687. doi: 10.1021/acs.jmedchem.7b01765. Epub 2018 Feb 6.

Discovery and Preclinical Development of IIIM-290, an Orally Active Potent Cyclin-Dependent Kinase Inhibitor.

Author information

1
Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
2
Academy of Scientific & Innovative Research, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
3
Preformulation Laboratory, PK-PD Toxicology & Formulation Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
4
Natural Products Chemistry Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
5
Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
6
Plant Biotechnology Division, CSIR-Indian Institute of Integrative Medicine , Canal Road, Jammu-180001, India.
7
Indian Pharmacopeia Commission , Sec-23, Raj Nagar, Ghaziabad-201002, India.

Abstract

Rohitukine (1), a chromone alkaloid isolated from Indian medicinal plant Dysoxylum binectariferum, has inspired the discovery of flavopiridol and riviciclib, both of which are bioavailable only via intravenous route. With the objective to address the oral bioavailability issue of this scaffold, four series of rohitukine derivatives were prepared and screened for Cdk inhibition and cellular antiproliferative activity. The 2,6-dichloro-styryl derivative IIIM-290 (11d) showed strong inhibition of Cdk-9/T1 (IC50 1.9 nM) kinase and Molt-4/MIAPaCa-2 cell growth (GI50 < 1.0 μM) and was found to be highly selective for cancer cells over normal fibroblast cells. It inhibited the cell growth of MIAPaCa-2 cells via caspase-dependent apoptosis. It achieved 71% oral bioavailability with in vivo efficacy in pancreatic, colon, and leukemia xenografts at 50 mg/kg, po. It did not have CYP/efflux-pump liability, was not mutagenic/genotoxic or cardiotoxic, and was metabolically stable. The preclinical data presented herein indicates the potential of 11d for advancement in clinical studies.

PMID:
29370702
DOI:
10.1021/acs.jmedchem.7b01765
[Indexed for MEDLINE]

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