Synthesis and biological evaluations of 3-substituted indolin-2-ones: a novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases.

3-Substituted indolin-2-ones have been designed and synthesized as a novel class of tyrosine kinase inhibitors which exhibit selectivity toward different receptor tyrosine kinases (RTKs). These compounds have been evaluated for their relative inhibitory properties against a panel of RTKs in intact cells. By modifying the 3-substituted indolin-2-ones, we have identified compounds which showed selective inhibition of the ligand-dependent autophosphorylation of various RTKs at submicromolar levels in cells. Structure-activity analysis for these compounds and their relative potency and selectivity to inhibit particular RTKs has determined that (1) 3-[(five-membered heteroaryl ring)methylidenyl]indolin-2-ones are highly specific against the VEGF (Flk-1) RTK activity, (2) 3-(substituted benzylidenyl)indolin-2-ones containing bulky group(s) in the phenyl ring at the C-3 position of indolin-2-ones showed high selectivity toward the EGF and Her-2 RTKs, and (3) the compound containing an extended side chain at the C-3 position of the indolin-2-one (16) exhibited high potency and selectivity when tested against the PDGF and VEGF (Flk-1) RTKs. Recent published crystallographic data for two of these 3-substituted indolin-2-ones provides a rationale to suggest that these compounds may bind in the ATP binding pocket of RTKs. The structure-activity analysis supports the use of subsets of these compounds as specific chemical leads for the development of RTK-specific drugs with broad application for the treatment of human diseases.

[1]  A. Ullrich,et al.  Flk-1 as a target for tumor growth inhibition. , 1996, Cancer research.

[2]  G. Mcmahon,et al.  Receptor tyrosine kinases as targets for inhibition of angiogenesis , 1997 .

[3]  P. Furet,et al.  4-(Phenylamino)pyrrolopyrimidines: potent and selective, ATP site directed inhibitors of the EGF-receptor protein tyrosine kinase. , 1996, Journal of medicinal chemistry.

[4]  C. Crestini,et al.  A New Efficient and Mild Synthesis of 2-Oxindoles by One-Pot Wolff- Kishner Like Reduction of Isatin Derivatives. , 1995 .

[5]  B. Welch.  The structure , 1992 .

[6]  W. Denny,et al.  Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. , 1996, Journal of medicinal chemistry.

[7]  S. Hubbard,et al.  Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. , 1997, Science.

[8]  J. Bishop.  The molecular genetics of cancer. , 1987, Science.

[9]  W. Denny,et al.  Tyrosine kinase inhibitors. 11. Soluble analogues of pyrrolo- and pyrazoloquinazolines as epidermal growth factor receptor inhibitors: synthesis, biological evaluation, and modeling of the mode of binding. , 1997, Journal of medicinal chemistry.

[10]  Peter Traxler,et al.  Protein tyrosine kinase inhibitors in cancer treatment , 1997 .

[11]  D. W. Fry,et al.  Inhibitors of tyrosine kinase , 1997, Current opinion in oncology.

[12]  P. Furet,et al.  Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimidines. , 1997, Journal of medicinal chemistry.

[13]  W. Denny,et al.  Tyrosine kinase inhibitors. 13. Structure-activity relationships for soluble 7-substituted 4-[(3-bromophenyl)amino]pyrido[4,3-d]pyrimidines designed as inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor. , 1997, Journal of medicinal chemistry.