Frank Boschelli

..When used in conjunction with appropriate secondary assays, this screen is a powerful cell-based tool for studying compounds that affect protein synthesis, folding, and degradation...

..This review will focus on preclinical studies supporting the clinical development of bosutinib for treatment of CML, with a discussion on the broader potential of this agent in other oncology indications...

..One of the analogues reported here exhibited in vivo activity comparable to that of SKI-606, a related 3-quinolinecarbonitrile currently in clinical trials...

..In an Src-transformed fibroblast xenograft model, both compounds exhibited a significant inhibition of tumor growth...

..When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth...

..These results support development of SKI-606 as a therapeutic agent for treatment of colorectal cancer...

..Compound 18, which has a 1-methylpiperidinemethoxy group at C-7, showed in vivo activity in a xenograft model...

..The kinase selectivity profile of 10 was similar to that of 1, with 10 also inhibiting the activity of Abl and Lck. When tested in a solid tumor xenograft model, 10 had comparable oral activity to that of 1...

..In addition, the fluoro group of 2 was readily displaced by primary and secondary amines to give 7-amino analogs. Two of these 7-amino analogs, 15 and 18, were potent Src inhibitors with in vivo activity...

..We disclose here a new highly efficient and versatile route to these compounds, which are also potent inhibitors of Abl kinase...

..Of these new analogs, compounds substituted at C-2 by a 3,5-furan or a 2,5-pyridine had the best activity in the Src enzyme and cell assays...

..The 7-alkene-3-quinolinecarbonitrile 20, a potent inhibitor of Src enzymatic and cellular activity with IC(50) values of 2.1 and 58 nM, respectively, had comparable efficacy to bosutinib in a colon tumor xenograft study...

..The lead compound, 17, showed potent activity in both the Src enzyme assay and cell assays, and demonstrated in vivo anti-tumor activity in a xenograft model...

..When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction...

..This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor...

..The best compounds are low nanomolar inhibitors of Src kinase, and have potent activity against Src-transformed fibroblast cells...

..Once daily oral administration of this compound at 100 mg/kg for 5 days causes complete regression of large K562 xenografts in nude mice...

..Several aniline substituents were surveyed, as well as water-solubilizing groups at the C-2 and N-3 positions. Potent Src inhibitors were identified, with N-3 providing the best position for an additional water-solubilizing group...

..The corresponding 4-(2,4-dichloro-5-methoxy)anilino-pyrimido[4,5-b]quinolines are much less effective Src inhibitors...

..Variation of the solubilizing amine tail or removal of the methoxy group from either C-6 of the quinoline core or C-5 of the aniline headpiece led to reduced activity...

..When suitably substituted, the resultant 7-phenylaminothieno[3,2-b]pyridine-6-carbonitrile analogues show potent inhibition of Src kinase activity...

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..Crystallographic studies show that these compounds bind in the ATP binding pocket interacting with the Asp93. Structure based optimization led to the identification of potent analogues, such as 13, with good biochemical profiles...

..The ethenyl and ethynyl groups were incorporated at C-7 utilizing a Stille, Heck, or Sonogashira coupling reaction...

..When the thiophene ring was substituted with a water-solubilizing group in a 2,5-, 3,5- or 2,4-pattern, potent inhibition of Src kinase activity was observed...

..Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay...

..For Src kinase inhibition, the best activity is obtained when both the 7- and 8-positions are substituted with alkoxy groups. Several of these kinase inhibitors show potent growth inhibitory activity in tumor cells...

..Now we have identified a series of 3-cyanoquinoline compounds that are low nanomolar inhibitors of IGF-1R. The strategies, synthesis, and SAR behind the cyanoquinoline scaffold will be discussed...

..The strategies, synthesis, and SAR behind this interesting kinase scaffold will be described...

..Under the same conditions, p16 binding to wild type Cdk4 was suppressed. Our findings show that the interaction of Cdc37 with its client protein kinases requires amino acid residues within a motif that is present in many protein kinases...