Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

Hwei-Ru Tsou; Gloria MacEwan; Gary Birnberg; George Grosu; Matthew G Bursavich; Joel Bard; Natasja Brooijmans; Lourdes Toral-Barza; Irwin Hollander; Tarek S Mansour; Semiramis Ayral-Kaloustian; Ker Yu

doi:10.1016/j.bmcl.2010.01.135

Discovery and optimization of 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR)

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2321-5. doi: 10.1016/j.bmcl.2010.01.135. Epub 2010 Feb 2.

Authors

Hwei-Ru Tsou¹, Gloria MacEwan, Gary Birnberg, George Grosu, Matthew G Bursavich, Joel Bard, Natasja Brooijmans, Lourdes Toral-Barza, Irwin Hollander, Tarek S Mansour, Semiramis Ayral-Kaloustian, Ker Yu

Affiliation

¹ Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, United States. tsouh@wyeth.com

PMID: 20188552
DOI: 10.1016/j.bmcl.2010.01.135

Abstract

We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.

MeSH terms

Adenosine Triphosphate / metabolism
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Benzofurans / chemistry*
Benzofurans / pharmacology*
Crystallography, X-Ray
Humans
Inhibitory Concentration 50
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
Intracellular Signaling Peptides and Proteins / metabolism*
Mice
Mice, Nude
Microsomes / metabolism
Models, Molecular
Neoplasms / drug therapy
Phosphatidylinositol 3-Kinases / chemistry
Phosphatidylinositol 3-Kinases / metabolism
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / metabolism*
Structure-Activity Relationship
TOR Serine-Threonine Kinases

Substances

Antineoplastic Agents
Benzofurans
Intracellular Signaling Peptides and Proteins
Protein Kinase Inhibitors
Adenosine Triphosphate
MTOR protein, human
mTOR protein, mouse
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases