Development of small molecules targeting the pseudokinase Her3

Sang Min Lim; Ting Xie; Kenneth D. Westover; Scott B. Ficarro; Hyun Seop Tae; Deepak Gurbani; Taebo Sim; Jarrod A. Marto; Pasi A. Jänne; Craig M. Crews; Nathanael S. Gray

doi:10.1016/j.bmcl.2015.04.103

Development of small molecules targeting the pseudokinase Her3

Sang Min Lim, Ting Xie, Kenneth D. Westover, Scott B. Ficarro, Hyun Seop Tae, Deepak Gurbani, Taebo Sim, Jarrod A. Marto, Pasi A. Jänne, Craig M. Crews, Nathanael S. Gray

Research output: Contribution to journal › Article › peer-review

55 Citations (Scopus)

Abstract

Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.

Original language	English
Article number	22688
Pages (from-to)	3382-3389
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2015.04.103
Publication status	Published - 2015 Jul 3

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Ltd.

Keywords

Cancer
Her3
Hydrophobic tagging
Pseudokinase
Pyrazolopyrimidine

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2015.04.103

Cite this

@article{c4a5644b0b3845fc94d63214c49e020a,

title = "Development of small molecules targeting the pseudokinase Her3",

abstract = "Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.",

keywords = "Cancer, Her3, Hydrophobic tagging, Pseudokinase, Pyrazolopyrimidine",

author = "Lim, {Sang Min} and Ting Xie and Westover, {Kenneth D.} and Ficarro, {Scott B.} and Tae, {Hyun Seop} and Deepak Gurbani and Taebo Sim and Marto, {Jarrod A.} and J{\"a}nne, {Pasi A.} and Crews, {Craig M.} and Gray, {Nathanael S.}",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd.",

year = "2015",

month = jul,

day = "3",

doi = "10.1016/j.bmcl.2015.04.103",

language = "English",

volume = "25",

pages = "3382--3389",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "16",

}

TY - JOUR

T1 - Development of small molecules targeting the pseudokinase Her3

AU - Lim, Sang Min

AU - Xie, Ting

AU - Westover, Kenneth D.

AU - Ficarro, Scott B.

AU - Tae, Hyun Seop

AU - Gurbani, Deepak

AU - Sim, Taebo

AU - Marto, Jarrod A.

AU - Jänne, Pasi A.

AU - Crews, Craig M.

AU - Gray, Nathanael S.

PY - 2015/7/3

Y1 - 2015/7/3

N2 - Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.

AB - Abstract Her3 is a member of the human epidermal growth factor receptor (EGFR) tyrosine kinase family, and it is often either overexpressed or deregulated in many types of human cancer. Her3 has not been the subject of small-molecule inhibitor development because it is a pseudokinase and does not possess appreciable kinase activity. We recently reported on the development of the first selective irreversible Her3 ligand (TX1-85-1) that forms a covalent bond with cysteine 721 which is unique to Her3 among all kinases. We also developed a bi-functional compound (TX2-121-1) containing a hydrophobic adamantane moiety and the same warhead of TX1-85-1 that is capable of inhibiting Her3-dependent signaling and growth. Here we report on the structure-based medicinal chemistry effort that resulted in the discovery of these two compounds.

KW - Cancer

KW - Her3

KW - Hydrophobic tagging

KW - Pseudokinase

KW - Pyrazolopyrimidine

UR - http://www.scopus.com/inward/record.url?scp=84933556335&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2015.04.103

DO - 10.1016/j.bmcl.2015.04.103

M3 - Article

C2 - 26094118

AN - SCOPUS:84933556335

SN - 0960-894X

VL - 25

SP - 3382

EP - 3389

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 16

M1 - 22688

ER -

Development of small molecules targeting the pseudokinase Her3

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this