Discovery of a Potent Class of PI3Kα Inhibitors
with Unique Binding Mode via Encoded Library Technology (ELT)

Yang, Hongfang; Medeiros, Patricia F.; Raha, Kaushik; Elkins, Patricia A.; Lind, Kenneth E.; Lehr, Ruth; Adams, Nicholas D.; Burgess, Joelle L; Schmidt, Stanley J; Knight, Steven D; Auger, Kurt R.; Schaber, Michael D.; Franklin, G Joseph; Ding, Yun; Delorey, Jennifer L; Centrella, Paolo
A.; Mataruse, Sibongile; Skinner, Steven R; Clark, Matthew A; Cuozzo, John
W.; Evindar, Ghotas

doi:10.1021/acsmedchemlett.5b00025

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Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

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Author(s): Hongfang Yang ^† , Patricia F. Medeiros ^† , Kaushik Raha ^‡ , Patricia Elkins ^‡ , Kenneth E. Lind ^† , Ruth Lehr ^§ , Nicholas D. Adams ^∥ , Joelle L. Burgess ^∥ , Stanley J. Schmidt ^∥ , Steven D. Knight ^∥ , Kurt R. Auger ^∥ , Michael D. Schaber ^⊥ , G. Joseph Franklin ^† , Yun Ding ^† , Jennifer L. DeLorey ^† , Paolo A. Centrella ^† , Sibongile Mataruse ^† , Steven R. Skinner ^† , Matthew A. Clark ^† , John W. Cuozzo ^† , Ghotas Evindar ^† ^,

Publication date (Electronic): 20 March 2015

Journal: ACS Medicinal Chemistry Letters

Publisher: American Chemical Society

Keywords: Encoded Library technology , ELT, PI3Kα, p110α, PI3K p110α (H1047R)

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Abstract

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.

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Most cited references 20

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Drugs for bad bugs: confronting the challenges of antibacterial discovery.

David J. Payne, Michael Gwynn, David Holmes … (2007)

The sequencing of the first complete bacterial genome in 1995 heralded a new era of hope for antibacterial drug discoverers, who now had the tools to search entire genomes for new antibacterial targets. Several companies, including GlaxoSmithKline, moved back into the antibacterials area and embraced a genomics-derived, target-based approach to screen for new classes of drugs with novel modes of action. Here, we share our experience of evaluating more than 300 genes and 70 high-throughput screening campaigns over a period of 7 years, and look at what we learned and how that has influenced GlaxoSmithKline's antibacterials strategy going forward.

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Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.

E. Walker, M Pacold, O Perisic … (2000)

The specific phosphoinositide 3-kinase (PI3K) inhibitors wortmannin and LY294002 have been invaluable tools for elucidating the roles of these enzymes in signal transduction pathways. The X-ray crystallographic structures of PI3Kgamma bound to these lipid kinase inhibitors and to the broad-spectrum protein kinase inhibitors quercetin, myricetin, and staurosporine reveal how these compounds fit into the ATP binding pocket. With a nanomolar IC50, wortmannin most closely fits and fills the active site and induces a conformational change in the catalytic domain. Surprisingly, LY294002 and the lead compound on which it was designed, quercetin, as well as the closely related flavonoid myricetin bind PI3K in remarkably different orientations that are related to each other by 180 degrees rotations. Staurosporine/PI3K interactions are reminiscent of low-affinity protein kinase/staurosporine complexes. These results provide a rich basis for development of isoform-specific PI3K inhibitors with therapeutic potential.

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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 .

Adrian Folkes, Khatereh Ahmadi, Wendy K Alderton … (2008)

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.

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Author and article information

Journal

Journal ID (nlm-ta): ACS Med Chem Lett

Journal ID (iso-abbrev): ACS Med Chem Lett

Journal ID (publisher-id): ml

Journal ID (coden): amclct

Title: ACS Medicinal Chemistry Letters

Publisher: American Chemical Society

ISSN (Electronic): 1948-5875

Publication date (Electronic): 20 March 2015

Publication date Collection: 14 May 2015

Publication date PMC-release: 20 March 2015

Volume: 6

Issue: 5

Pages: 531-536

Affiliations

[† ]MDR (Molecular Discovery Research) Boston, Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States

[2.0] ^‡Computational and Structural Chemistry, Platform Technology and Science, ^§Biological Reagents and Assay Development, Platform Technology and Science, ^∥Oncology Research, and ^⊥Screening and Compound Profiling, Platform Technology and Science, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States

Author notes

[* ]E-mail: ghotas.x.evindar@ 123456gsk.com .

Article

DOI: 10.1021/acsmedchemlett.5b00025

PMC ID: 4434457

PubMed ID: 26005528

SO-VID: 369863f5-2907-4866-91bd-f40d535f30dc

License:

This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

History

Date received : 19 January 2015

Date accepted : 20 March 2015

Custom metadata

document-id-old-9 ml5b00025

document-id-new-14 ml-2015-000252

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ScienceOpen disciplines: Pharmaceutical chemistry

Keywords: encoded library technology,elt,pi3kα,p110α,pi3k p110α (h1047r)

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ScienceOpen disciplines: Pharmaceutical chemistry

Keywords: encoded library technology, elt, pi3kα, p110α, pi3k p110α (h1047r)

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Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

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Abstract

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Most cited references 20

Drugs for bad bugs: confronting the challenges of antibacterial discovery.

Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine.

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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Cited by 13

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