Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency.

HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.

[1]  A. Bridges,et al.  Tyrosine kinase inhibitors. 16. 6,5,6-tricyclic benzothieno[3, 2-d]pyrimidines and pyrimido[5,4-b-] and -[4,5-b]ĭndoles as potent inhibitors of the epidermal growth factor receptor tyrosine kinase. , 1999, Journal of medicinal chemistry.

[2]  H. Hsieh,et al.  A cell-based high-throughput screen for epidermal growth factor receptor pathway inhibitors. , 2008, Analytical biochemistry.

[3]  Ramaswamy Nilakantan,et al.  Synthesis and Structure−Activity Relationships of 6,7-Disubstituted 4-Anilinoquinoline-3-carbonitriles. The Design of an Orally Active, Irreversible Inhibitor of the Tyrosine Kinase Activity of the Epidermal Growth Factor Receptor (EGFR) and the Human Epidermal Growth Factor Receptor-2 (HER-2) , 2003 .

[4]  Santhosh Kumar Chittimalla,et al.  Fast-forwarding hit to lead: aurora and epidermal growth factor receptor kinase inhibitor lead identification. , 2010, Journal of medicinal chemistry.

[5]  Ramaswamy Nilakantan,et al.  Antitumor Activity of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase , 2004, Cancer Research.

[6]  M. Meyerson,et al.  BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models , 2008, Oncogene.

[7]  M. Fukuoka,et al.  EKB-569, a new irreversible epidermal growth factor receptor tyrosine kinase inhibitor, with clinical activity in patients with non-small cell lung cancer with acquired resistance to gefitinib. , 2006, Lung cancer.

[8]  A. Wissner,et al.  The Development of HKI‐272 and Related Compounds for the Treatment of Cancer , 2008, Archiv der Pharmazie.

[9]  W. Denny,et al.  Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Daniel A. Haber,et al.  Epidermal growth factor receptor mutations in lung cancer , 2007, Nature Reviews Cancer.

[11]  M. Meyerson,et al.  The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP , 2008, Proceedings of the National Academy of Sciences.

[12]  Ramaswamy Nilakantan,et al.  Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. , 2005, Journal of medicinal chemistry.

[13]  A. Bridges,et al.  Enantioselective inhibition of the epidermal growth factor receptor tyrosine kinase by 4-(alpha-phenethylamino)quinazolines. , 1995, Bioorganic & medicinal chemistry.

[14]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[15]  J. Mestan,et al.  AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. , 2004, Cancer research.

[16]  G. Tortora,et al.  EGFR antagonists in cancer treatment. , 2008, The New England journal of medicine.