Pyrido[2,3- d ]pyrimidin-7-ones as Specific Inhibitors of Cyclin-Dependent Kinase 4

Department of Medicinal Chemistry, and Cancer Pharmacology, Pfizer Global Research and Development, Michigan Laboratories, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.45). 05/2005; 48(7):2371-87. DOI: 10.1021/jm049355+
Source: PubMed


Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pyrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.

14 Reads
  • Source
    • "Pyridopyrimidines are nitrogen-bearing heterocyclic compounds which have various pharmaceutical applications. In particular, pyrido[2,3-d]pyrimidine derivatives show variable biological activities such as anticancer agents inhibiting dihydrofolate reductases or tyrosine kinases [1] [2] [3], antitumor [4] [5], antiviral [6], antihistaminic [7], anti-inflammatory [8], antibacterial [9] [10] [11] [12], and also act as cyclin-dependent kinase 4 inhibitors [13]. This structural moiety is present in ramastine (anti-allergic) [14] and pirenperone (tranquilizer) [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Indeno[2’,1’:5,6]pyrido[2,3-d]pyrimidin-4,6-(5H,11H)dion derivatives were synthesized regioselectively in high yields by a three-component reaction of 1,3-indanedione , aromatic aldehydes and 2,6-diaminopyrimidin-4(3H)-one in the presence of 1,2–dimethyl-N-butanesulfonic acid imidazolium hydrogen sulfate ([DMBSI]HSO4) ionic liquid as green and reusable catalyst. This protocol produced the desired products in high yields (87-95 %) and short reaction times (3-6 min).
    Full-text · Article · Dec 2014 · Journal of Saudi Chemical Society
  • Source
    • "This is due by their wide range of biological activities, particularly in cancer and virus research (Baba et al., 1987; Gangjee et al., 1995). Pyrido[2,3-d] pyrimidines were reported to exhibit antitumor activity which may be attributed to inhibition of cyclin dependent kinase (Toogood et al., 2005; VanderWel et al., 2005), check point kinase (Palmer et al., 2005) or mammalian target of rapamycin (Malagu et al., 2009). In addition , thienopyrimidine derivatives showed promising biological (Devani et al., 1976) and anticancer activity (Dai et al., 2005; Rheault et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: New series of pyrido[3',2':4,5]thieno[3,2-d]pyrimidines (7a,b) and thieno[2,3-b:4,5-b'] dipyridine (11a-c) were synthesized from 4-aryl-6-(4-chlorophenyl)-2-thioxo-1,2-dihydro pyridine-3-carbonitriles 4a,b via application of Thorpe-Zielger reaction. The novel target compounds were evaluated in vitro for their anticancer activity against human breast adenocarcinoma MCF-7 and colon carcinoma cell line (HCT 116). Most of the tested compounds exploited potent to moderate growth inhibitory activity, in particular compound 11d, which exhibited superior potency to the reference drug Doxorubicin (IC(50) = 5.95, 6.09 and 8.48, 8.15 μM, respectively). The structures of the compounds obtained were determined by spectroscopic data.
    Full-text · Article · Nov 2012 · Archives of Pharmacal Research
  • Source
    • "PD 0332991, a pyrido[2,3-δ]pyrimidine-7-one, is a selective inhibitor of cdk4 and cdk675. In low micromolar concentrations in in vitro and xenograft models, it inhibited a panel of Rb-positive solid tumour cell lines76,77. The drug was also tested in vitro against mantle cell lymphoma (mcl)78. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases (cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription. Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit maximum therapeutic effect.
    Preview · Article · Apr 2009 · Current Oncology
Show more