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Benzopyranones and Benzothiopyranones: A Class of Tyrosine Protein Kinase Inhibitors with Selectivity for the v-abl Kinase

Pharmaceuticals Division, Oncology and Virology Research Department, Ciba-Geigy Ltd., K-125.4.20, CH-4002 Basel, Switzerland

Abelson murine leukemia virus is an acutely transforming replication-defective virus which encodes a transforming protein with tyrosine-specific protein kinase activity. A variety of benzopyranone and benzothiopyranone derivatives have been identified which selectively inhibit the v-abl tyrosine protein kinase with 50% inhibitory concentrations ranging from 1 to 30 µM. The most active derivative inhibited v-abl with a K_i value of 0.9 µM. Active derivatives showed selectivity for the v-abl tyrosine protein kinase relative to the epidermal growth factor receptor tyrosine protein kinase (50% inhibitory concentration > 100 µM). Protein kinase C and protein kinase A, two members of the serine/threonine protein kinase family, were not inhibited by benzopyranones or benzothiopyranones (50% inhibitory concentration > 100 µM). Kinetically, a representative derivative (compound 2) showed competitivity with respect to ATP and noncompetitive behavior with respect to the exogenous peptide substrate. Autophosphorylation of p120^v-abl and recombinant p70^v-abl tyrosine protein kinases were also inhibited by benzopyranones and benzothiopyranones in vitro. When tested in Abelson murine leukemia virus-transformed BALB/c cell, active benzopyranone and benzothiopyranone derivatives inhibited tyrosine phosphorylation of cellular proteins by the v-abl tyrosine protein kinase.

¹ To whom requests for reprints should be addressed.

Received 3/ 2/92. Accepted 6/ 8/92.

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