Bioorganic and Medicinal Chemistry Letters

, volume 23 , issue 11 , pages 3149-3153

Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design

Wendy Isobel Young ¹

Steven Magnuson ¹

Rich Pastor ¹

Eric Fan ²

Huiyong Hu ¹

Vickie Tsui ¹

Wei Deng ³

Jeremy Murray ¹

Micah Steffek ⁴

Heidi Ackerly Wallweber ¹

John Moffat ¹

Jason Drummond ¹

Grace Chan ¹

Eric Harstad ¹

Allen J Ebens ¹

Hide authors affiliations Show authors affiliations: 4 affiliations

Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, United States. |

Campbell Alliance, 2545 West Hillcrest Drive, Thousand Oaks, CA 94080, United States |

Merck Sharp & Dohme R&D, 2/F Building 21, 10 Jiuxianqiao Rd, Universal Business Park, Chaoyang District, Beijing 100015, China |

⁴

Novartis Institutes for Biomedical Research, 4560 Horton Street, Emeryville, CA 94608, United States |

Publication type: Journal Article

Publication date: 2013-06-01

Elsevier

Bioorganic and Medicinal Chemistry Letters

scimago Q2

wos Q2

SJR: 0.472

CiteScore: 5.1

Impact factor: 2.2

ISSN: 0960894X, 14643405

DOI: 10.1016/j.bmcl.2013.04.020

Copy DOI

PubMed ID: 23623490

Organic Chemistry

Drug Discovery

Biochemistry

Molecular Biology

Pharmaceutical Science

Clinical Biochemistry

Molecular Medicine

Abstract

Pim kinases are promising targets for the development of cancer therapeutics. Among the three Pim isoforms, Pim-2 is particularly important in multiple myeloma, yet is the most difficult to inhibit due to its high affinity for ATP. We identified compound 1 via high throughput screening. Using property-based drug design and co-crystal structures with Pim-1 kinase to guide analog design, we were able to improve potency against all three Pim isoforms including a significant 10,000-fold gain against Pim-2. Compound 17 is a novel lead with low picomolar potency on all three Pim kinase isoforms.

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GOST |

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GOST Copy

Young W. I. et al. Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design // Bioorganic and Medicinal Chemistry Letters. 2013. Vol. 23. No. 11. pp. 3149-3153.

GOST all authors (up to 50) Copy

Young W. I., Magnuson S., Pastor R., Fan E., Hu H., Tsui V., Deng W., Murray J., Steffek M., Wallweber H. A., Moffat J., Drummond J., Chan G., Harstad E., Ebens A. J. Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design // Bioorganic and Medicinal Chemistry Letters. 2013. Vol. 23. No. 11. pp. 3149-3153.

RIS |

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RIS Copy

TY - JOUR

DO - 10.1016/j.bmcl.2013.04.020

UR - https://doi.org/10.1016/j.bmcl.2013.04.020

TI - Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design

T2 - Bioorganic and Medicinal Chemistry Letters

AU - Young, Wendy Isobel

AU - Magnuson, Steven

AU - Pastor, Rich

AU - Fan, Eric

AU - Hu, Huiyong

AU - Tsui, Vickie

AU - Deng, Wei

AU - Murray, Jeremy

AU - Steffek, Micah

AU - Wallweber, Heidi Ackerly

AU - Moffat, John

AU - Drummond, Jason

AU - Chan, Grace

AU - Harstad, Eric

AU - Ebens, Allen J

PY - 2013

DA - 2013/06/01

PB - Elsevier

SP - 3149-3153

IS - 11

VL - 23

PMID - 23623490

SN - 0960-894X

SN - 1464-3405

ER -

BibTex |

Cite this

BibTex (up to 50 authors) Copy

@article{2013_Young,

author = {Wendy Isobel Young and Steven Magnuson and Rich Pastor and Eric Fan and Huiyong Hu and Vickie Tsui and Wei Deng and Jeremy Murray and Micah Steffek and Heidi Ackerly Wallweber and John Moffat and Jason Drummond and Grace Chan and Eric Harstad and Allen J Ebens},

title = {Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design},

journal = {Bioorganic and Medicinal Chemistry Letters},

year = {2013},

volume = {23},

publisher = {Elsevier},

month = {jun},

url = {https://doi.org/10.1016/j.bmcl.2013.04.020},

number = {11},

pages = {3149--3153},

doi = {10.1016/j.bmcl.2013.04.020}

}

MLA

Cite this

MLA Copy

Young, Wendy Isobel, et al. “Discovery of novel pyrazolo[1,5-a]pyrimidines as potent pan-Pim inhibitors by structure- and property-based drug design.” Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 11, Jun. 2013, pp. 3149-3153. https://doi.org/10.1016/j.bmcl.2013.04.020.

Publisher

Elsevier

Journal

Bioorganic and Medicinal Chemistry Letters

scimago Q2

wos Q2

SJR

0.472

CiteScore

5.1

Impact factor

2.2

ISSN

0960894X (Print)

14643405 (Electronic)