Diane H. Boschelli

SKI-606, a Src/Abl Inhibitor with In vivo Activity in Colon Tumor Xenograft Models

Src up-regulation is a common event in human cancers. In colorectal cancer, increased Src levels are an indicator of poor prognosis, and progression to metastatic disease is associated with substantial increases in Src activity. Therefore, we examined the activity of SKI-606, a potent inhibitor of Src and Abl kinases, against colon tumor lines in vitro and in s.c. tumor xenograft models. SKI-606 inhibited Src autophosphorylation with an IC(50) of approximately 0.25 micromol/L in HT29 cells. Phosphorylation of Tyr(925) of focal adhesion kinase, a Src substrate, was reduced by similar concentrations of inhibitor. Antiproliferative activity on plastic did not correlate with Src inhibition in either HT29 or Colo205 cells (IC(50)s, 1.5 and 2.5 micromol/L, respectively), although submicromolar concentrations of SKI-606 inhibited HT29 cell colony formation in soft agar. SKI-606 also caused loosely aggregated Colo205 spheroids to condense into compact spheroids. On oral administration to nude mice at the lowest efficacious dose, peak plasma concentrations of approximately 3 micromol/L, an oral bioavailability of 18%, and a t(1/2) of 8.6 hours were observed. SKI-606 was orally active in s.c. colon tumor xenograft models and caused substantial reductions in Src autophosphorylation on Tyr(418) in HT29 and Colo205 tumors. SKI-606 inhibited HT29 tumor growth on once daily administration, whereas twice daily administration was necessary to inhibit Colo205, HCT116, and DLD1 tumor growth. These results support development of SKI-606 as a therapeutic agent for treatment of colorectal cancer.

Inhibitors of Src tyrosine kinase: the preparation and structure–activity relationship of 4-anilino-3-cyanoquinolines and 4-anilinoquinazolines

Src is a nonreceptor tyrosine kinase involved in signaling pathways that control proliferation, migration, and angiogenesis. Increased Src expression and activity are associated with an increase in tumor malignancy and poor prognosis. Several quinolines and quinazolines were identified as potent and selective inhibitors of Src kinase activity.

Inhibition of Src kinase activity by 4-anilino-7-thienyl-3-quinolinecarbonitriles

Based on a screening lead from a yeast-based assay to identify Src family kinase inhibitors, a series of 4-anilino-7-thienyl-3-quinolinecarbonitriles was prepared. 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.

Synthesis and evaluation of 4-Anilino-6,7-dialkoxy-3-quinolinecarbonitriles as inhibitors of kinases of the Ras-MAPK signaling cascade

4-[3-Chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)]anilino-6,7-diethoxy-3-quinolinecarbonitrile (3) was identified as a MEK1 kinase inhibitor with exceptional activity against LoVo cells. The structure-activity relationships of the C-4 aniline substituents were explored, and water-solubilizing groups were added at the C-7 position to improve physical properties. Secondary cellular assays revealed that a compound possessing the appropriate aniline substituents inhibited MEK1 as well as MAPK phosphorylation, thereby acting as a dual inhibitor of the Ras-MAPK signaling cascade.

Synthesis and biological properties of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid

The synthesis of the antifolate 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF) has been modified. It is prepared from 2-acetamido-6-formyl-4(3H)-pyrido[2,3-b]pyrimidone and [P-(N-[1,3-bis(ethoxycarbonyl)propan-1-yl]aminocarbonyl)] phenylmethyl]-triphenylphosphonium bromide. The synthesis proceeds via a sodium hydride promoted Wittig condensation in 1-methyl-2-pyrrolidone followed by catalytic reduction, mild base hydrolysis, and acid precipitation of the product. Synthesis of DDATHF is achieved in a total of seven steps from commercially available reagents. DDATHF is transported effectively into CCRF-CEM cells and inhibits growth of both human (CEM) and murine (L1210) cells in culture. Studies reported here support the view that methotrexate and DDATHF are transported via a shared transport mechanism.

Inhibition of Src kinase activity by 4-anilino-5,10-dihydro-pyrimido[4,5-b]quinolines

4-(2,4-Dichloro-5-methoxy)anilino-5,10-dihydropyrimido[4,5-b]quinolines are potent inhibitors of Src kinase and Src cellular activity while having no effect on Fyn cellular activity. The corresponding 4-(2,4-dichloro-5-methoxy)anilino-pyrimido[4,5-b]quinolines are much less effective Src inhibitors.

The Stereospecific Cyclization of A Threo α-Benzamide Alcohol to A Cis N-Acyl Aziridine

Abstract Treatment of threo α-benzamide alcohol 3b with triphenylphosphine and diethyl azodicarboxylate gave solely the cis N-acyl aziridine 5b.

An improved synthesis of glycinamide ribonucleotide

Abstract Glycinamide ribonucleotide (GAR) was obtained in 7 steps in 15% yield from a commercially available ribose derivative.