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PMID: 18754654 Published · ppublish English Journal Article

The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .

Journal of medicinal chemistry ·Vol. 51 ·No. 18 ·2008-09-25 ·Pages 5522-32

Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, Kugendradas A, Lensun L, Moore P, Olivero AG, Pang J, Patel S, Pergl-Wilson GH, Raynaud FI, Robson A, Saghir N, Salphati L, Sohal S, Ultsch MH, Valenti M, Wallweber HJ, Wan NC, Wiesmann C, Workman P, Zhyvoloup A, Zvelebil MJ, Shuttleworth SJ

Abstract

Phosphatidylinositol-3-kinase (PI3K) is an important target in cancer due to the deregulation of the PI3K/ Akt signaling pathway in a wide variety of tumors. A series of thieno[3,2-d]pyrimidine derivatives were prepared and evaluated as inhibitors of PI3 kinase p110alpha. The synthesis, biological activity, and further profiling of these compounds are described. This work resulted in the discovery of 17, GDC-0941, which is a potent, selective, orally bioavailable inhibitor of PI3K and is currently being evaluated in human clinical trials for the treatment of cancer.

MeSH Terms

Administration, Oral Antineoplastic Agents/administration & dosage,pharmacokinetics,pharmacology,therapeutic use Biological Availability Cell Line, Tumor Drug Screening Assays, Antitumor Enzyme Inhibitors/administration & dosage,pharmacokinetics,pharmacology,therapeutic use Humans Indazoles/administration & dosage,pharmacokinetics,pharmacology,therapeutic use Magnetic Resonance Spectroscopy Molecular Structure Neoplasms/drug therapy Phosphoinositide-3 Kinase Inhibitors Sulfonamides/administration & dosage,pharmacokinetics,pharmacology,therapeutic use

Chemicals

2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine Antineoplastic Agents Enzyme Inhibitors Indazoles Phosphoinositide-3 Kinase Inhibitors Sulfonamides

Authors & Affiliations

34 authors, click to expand affiliations / ORCID

Folkes Adrian J

Piramed Pharma, 957 Buckingham Avenue, Slough, Berks SL1 4NL, United Kingdom. [email protected]

Ahmadi Khatereh

Alderton Wendy K

Alix Sonia

Baker Stewart J

Box Gary

Chuckowree Irina S

Clarke Paul A

Depledge Paul

Eccles Suzanne A

Friedman Lori S

Hayes Angela

Hancox Timothy C

Kugendradas Arumugam

Lensun Letitia

Moore Pauline

Olivero Alan G

Pang Jodie

Patel Sonal

Pergl-Wilson Giles H

Raynaud Florence I

Robson Anthony

Saghir Nahid

Salphati Laurent

Sohal Sukhjit

Ultsch Mark H

Valenti Melanie

Wallweber Heidi J A

Wan Nan Chi

Wiesmann Christian

Workman Paul

Zhyvoloup Alexander

Zvelebil Marketa J

Shuttleworth Stephen J

Article Info

Journal

Journal of medicinal chemistry

Abbr.

J Med Chem

ISSN

1520-4804

DOI

10.1021/jm800295d

[email protected]

Published

2008-09-25

Pages

5522-32

Language

English

Region

United States

NLM ID

9716531

Subset

Databases

PDB

3DBS

External Links

PubMed source DOI: 10.1021/jm800295d View journal details

Analysis Services

The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer .

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