Macrocyclic hedgehog pathway inhibitors: Optimization of cellular activity and mode of action studies

ACS Medicinal Chemistry Letters

Volumn 3, Issue 10, 2012, Pages 808-813

  Dockendorff, Chris ^a   Nagiec, Marek M ^a   Weïwer, Michel ^a   Buhrlage, Sara ^a   Ting, Amal ^a   Nag, Partha P ^a   Germain, Andrew ^a   Kim, Han Je ^a   Youngsaye, Willmen ^a   Scherer, Christina ^a   Bennion, Melissa ^a   Xue, Linlong ^a   Stanton, Benjamin Z ^a   Lewis, Timothy A ^a   MacPherson, Lawrence ^a   Palmer, Michelle ^a   Foley, Michael A ^a   Perez, José R ^a   Schreiber, Stuart L ^a  

^a BROAD INSTITUTE OF MIT AND HARVARD   (United States)

Author keywords

C3H10T1 2; diversity oriented synthesis (DOS); macrocycle; Smoothened antagonist; Sonic Hedgehog pathway

Indexed keywords

ALKADIENE; ALKALINE PHOSPHATASE; AMINOALCOHOL; ANTINEOPLASTIC AGENT; BRD 6851; CARBOXYLIC ACID; CYCLOPAMINE; EPHEDRINE DERIVATIVE; MACROCYCLIC COMPOUND; NITROGEN; OXYGEN; PROTEIN INHIBITOR; PROTEIN PATCHED; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR GLI1; UNCLASSIFIED DRUG; VISMODEGIB;

ARTICLE; BINDING SITE; CELL ACTIVITY; CELL DIFFERENTIATION; CONCENTRATION RESPONSE; DRUG SYNTHESIS; ENZYME INDUCTION; IC 50; KNOCKOUT GENE; LIPOPHILICITY; METHYLATION; PRIORITY JOURNAL; RING CLOSING METATHESIS; SIGNAL TRANSDUCTION; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

EID: 84867355834     PISSN: None     EISSN: 19485875     Source Type: Journal    
DOI: 10.1021/ml300172p     Document Type: Article

References (27)

1. See, for example, Ng, J. M. Y.; Curran, T. The Hedgehog's tale: Developing strategies for targeting cancer Nat. Rev. Cancer 2011, 11, 493-501
2. Firestone, A. J.; Chen, J. K. Small-molecule inhibitors of the Hedgehog pathway. In Hedgehog Signaling Activation in Human Cancer and Its Clinical Applications; Xie, J., Ed.; Springer: New York, NY, 2011; pp 163-186.
3. Peukert, S.; Miller-Moslin, K. Small-molecule inhibitors of the Hedgehog signaling pathway as cancer therapeutics ChemMedChem 2010, 5, 500-512
4. Tremblay, M. R.; McGovern, K.; Read, M. A.; Castro, A. C. New developments in the discovery of small molecule Hedgehog pathway antagonists Curr. Opin. Chem. Biol. 2010, 14, 428-435
5. Stanton, B. Z.; Peng, L. F. Small-molecule modulators of the Sonic Hedgehog signaling pathway Mol. BioSyst. 2010, 6, 44-54
6. Mahindroo, N.; Punchihewa, C.; Fujii, N. Hedgehog-Gli signaling pathway inhibitors as anticancer agents J. Med. Chem. 2009, 52, 3829-3845
7. Yauch, R. L. A paracrine requirement for hedgehog signalling in cancer Nature 2008, 455, 406-410
8. Nolan-Stevaux, O. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation Genes Dev. 2009, 23, 24-36
9. Tian, H. Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis Proc. Natl. Acad. Sci. 2009, 106, 4254-4259
10. Theunissen, J.-W.; de Sauvage, F. J. Paracrine Hedgehog signaling in cancer Cancer Res. 2009, 69, 6007-6010
11. Tremblay, M. R. Discovery of a potent and orally active Hedgehog pathway antagonist (IPI-926) J. Med. Chem. 2009, 52, 4400-4418
12. Pan, S. Discovery of NVP-LDE225, a potent and selective Smoothened antagonist ACS Med. Chem. Lett. 2010, 1, 130-134
13. Munchhof, M.; Li, Q.; Shavnya, A.; Borzillo, G. V.; Boyden, T. L.; Jones, C. S.; LaGreca, S. D.; Martinez-Alsina, L.; Patel, N.; Pelletier, K.; Reiter, L. A.; Robbins, M. D.; Tkalcevic, G. T. Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened ACS Med. Chem. Lett. 2012, 3, 106-111
14. Rudin, C. M.; Hann, C. L.; Laterra, J.; Yauch, R. L.; Callahan, C. A.; Fu, L.; Holcomb, T.; Stinson, J.; Gould, S. E.; Coleman, B.; LoRusso, P. M.; Von Hoff, D. D.; de Sauvage, F. J.; Low, J. A. Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449 N. Engl. J. Med. 2009, 361, 1173-1178
15. Stanton, B. Z.; Peng, L. F.; Maloof, N.; Nakai, K.; Wang, X.; Duffner, J. L.; Taveras, K. M.; Hyman, J. M.; Lee, S. W.; Koehler, A. N.; Chen, J. K.; Fox, J. L.; Mandinova, A.; Schreiber, S. L. A small molecule that binds Hedgehog and blocks its signaling in human cells Nat. Chem. Biol. 2009, 5, 154-156
16. Peng, L. F.; Stanton, B. Z.; Maloof, N.; Wang, X.; Schreiber, S. L. Syntheses of aminoalcohol-derived macrocycles leading to a small-molecule binder to and inhibitor of Sonic Hedgehog Bioorg. Med. Chem. Lett. 2009, 19, 6319-6325
17. Taipale, J.; Chen, J. K.; Cooper, M. K.; Wang, B.; Mann, R. K.; Milenkovic, L.; Scott, M. P.; Beachy, P. A. The effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine Nature 2000, 406, 1005-1009
18. Nielsen, T. E.; Schreiber, S. L. Towards the optimal screening collection: A synthesis strategy Angew. Chem., Int. Ed. 2007, 47, 48-56
19. Lee, D.; Sello, J. K.; Schreiber, S. L. A strategy for macrocyclic ring closure and functionalization aimed toward split-pool syntheses J. Am. Chem. Soc. 1999, 121, 10648-10649
20. Frank-Kamenetsky; Zhang, X. M.; Bottega, S.; Guicherit, O.; Wichterle, H.; Dudek, H.; Bumcrot, D.; Wang, F. Y.; Jones, S.; Shulok, J.; Rubin, L. L.; Porter, J. A. Small-molecule modulators of Hedgehog signaling: Identification and characterization of Smoothened agonists and antagonists J. Biol. 2002, 1, 10.1-10.19
21. Chen, J. K.; Taipale, J.; Young, K. E.; Maiti, T.; Beachy, P. A. Small molecule modulation of Smoothened activity Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 14071-14076
22. Rominger, C. M. Evidence for allosteric interactions of antagonist binding to the Smoothened receptor J. Pharmacol. Exp. Ther. 2009, 329, 995-1005
23. Taylor, P.; Insel, P. A. Quantitation of pharmacologic antagonism. In Principles of Drug Action: The Basis of Pharmacology; Pratt, W. P.; Taylor, P., Eds.; Churchill Livingstone: New York, 1990; pp 61-66.
24. Wu, X.; Ding, S.; Ding, Q.; Gray, N. S.; Schultz, P. G. A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells J. Am. Chem. Soc. 2002, 124, 14520-14521
25. Sinha, S.; Chen, J. K. Purmorphamine activates the Hedgehog pathway by targeting Smoothened Nature Chem. Biol. 2002, 2, 29-30
26. Tao, H.; Jin, Q.; Koo, D.-I.; Liao, X.; Englund, N. P.; Wang, Y.; Ramamurthy, A.; Schultz, P. G.; Dorsch, M.; Kelleher, J.; Xu, W. Small molecule antagonists in distinct binding modes inhibit drug-resistant mutant of Smoothened Chem. Biol. 2011, 18, 432-437
27. Dijkgraaf, G. J. P.; Alicke, B.; Weinmann, L.; Januario, T.; West, K.; Modrusan, Z.; Burdick, D.; Goldsmith, R.; Robarge, K.; Sutherlin, D.; Scales, S. J.; Gould, S. E.; Yauch, R. L.; de Sauvage, F. J. Small molecule inhibition of GDC-0449 refractory Smoothened mutants and downstream mechanisms of drug resistance Cancer Res. 2011, 71, 435-444