A novel series of pyrazolobenzodiazepines 3 has been identified as potent inhibitors of cyclin-dependent kinase 2 (CDK2). Their synthesis and structure-activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK2 activity in vitro, and block cell cycle progression in human tumor cell lines. Further exploration has revealed that this class of compounds inhibits several kinases that play critical roles in cancer cell growth and division as well as tumor angiogenesis. Together, these properties suggest a compelling basis for their use as antitumor agents. (c) 2010 Elsevier Ltd. All rights reserved.

A novel series of quinolinyl-methylene-thiazolinones has been identified as potent and selective cyclin-dependent kinase 1 (CDK1) inhibitors. Their synthesis and structure activity relationships (SAR) are described. Representative compounds from this class reversibly inhibit CDK1 activity in vitro, and block cell cycle progression in human tumor cell lines, suggesting a potential use as antitumor agents.

RO4396686 is a small molecule KDR, FGFR, and PDGFR inhibitor with good pharmacokinetic properties in rodents. In a mouse corneal neovascularization assay, this compound inhibited VEGF-induced angiogenesis. Tested in a H460a xenograft tumor model this agent effected significant tumor growth inhibition at doses as low as 50 mg/kg.

2478 The pyrimidopyrimidine moiety represents a core structure that is a useful template for the design of a variety of tyrosine kinase inhibitors. From high throughput screening, a pyrimidopyrimidine analogue was identified as a dual inhibitor of the growth factor receptors KDR (IC50 = 40 nM) and FGFR-1 (IC50 = 210 nM). This analogue was a significantly less potent inhibitor of other kinases tested (LCK, IC50 = 8 μM; CDK2 and p38, IC50 > 25 μM). The crystal structure of the src-family tyrosine kinase LCK with a closely related analogue bound was determined, elucidating the binding mode of the pyrimidopyrimidines. From these data, the ligand was docked into the ATP binding pocket of KDR. Based on this model a series of analogues were designed and synthesized to study the structure activity relationship. These compounds showed excellent activity in in vitro kinase assays and also in growth-factor stimulated HUVEC proliferation assays. In vivo experiments demonstrated significant inhibition of angiogenesis in the corneal pocket assay (CPA) and tumor growth inhibition in xenograft models for a number of these compounds. Structure activity relationship of these pyrimidopyrimidine compounds will be discussed.

A novel class of 3,5,6-trisubstituted naphthostyril analogues was designed and synthesized to study the structure-activity relationship for inhibition of cyclin-dependent kinase 2 (CDK2). These compounds, particularly molecules with side-chain modifications providing additional hydrogen bonding capability, were demonstrated to be potent CDK2 inhibitors with cellular activities consistent with CDK2 inhibition. These molecules inhibited tumor cell proliferation and G1-S and G2-M cell-cycle progression in vitro. The X-ray crystal structure of a 2-aminoethyleneamine derivative bound to CDK2, refined to 2.5A resolution, is presented.

A one-pot synthesis of 3,5,6-trisubstituted naphthostyrils is described. Addition of organometallic reagents to β-iodovinyl ketone 1 followed by elimination gave the Z-form β-alkyl vinyl ketone 15. Intramolecular cyclization of 15 under the reaction conditions afforded 3,5,6-trisubstituted naphthostyrils 4.

3-Pyrrolyl-6-fluoro-naphthostyril 13 was synthesized via a base-catalyzed intramolecular cyclization of oxindole precursor 2 (Y=H). Derivatization of 2 (Y=I) through a one-pot reaction give 5-substituted naphthostyrils. This method allows convenient access to 3,5,6-trisubstituted naphthostyrils which may serve as a new template for CDK2 inhibition.