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 journalArticle

18 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 languageEnglish
Article number22688
Pages (from-to)3382-3389
Number of pages8
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number16
DOIs
Publication statusPublished - 2015 Jul 3
Externally publishedYes

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Phosphotransferases
Adamantane
Molecules
Covalent bonds
Pharmaceutical Chemistry
Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Cysteine
Ligands
Growth
Neoplasms
TX1-85-1
N-(2-(4-(3-(3-acrylamido-4-phenoxyphenyl)-4-amino-1H-pyrazolo(3,4-d)pyrimidin-1-yl)piperidin-1-yl)ethyl)-4-(1-adamantanyl)-2-methylbutanamide

Keywords

  • Cancer
  • Her3
  • Hydrophobic tagging
  • Pseudokinase
  • Pyrazolopyrimidine

ASJC Scopus subject areas

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

Cite this

Lim, S. M., Xie, T., Westover, K. D., Ficarro, S. B., Tae, H. S., Gurbani, D., ... Gray, N. S. (2015). Development of small molecules targeting the pseudokinase Her3. Bioorganic and Medicinal Chemistry Letters, 25(16), 3382-3389. [22688]. https://doi.org/10.1016/j.bmcl.2015.04.103

Development of small molecules targeting the pseudokinase Her3. / Lim, Sang Min; Xie, Ting; Westover, Kenneth D.; Ficarro, Scott B.; Tae, Hyun Seop; Gurbani, Deepak; Sim, Taebo; Marto, Jarrod A.; Jänne, Pasi A.; Crews, Craig M.; Gray, Nathanael S.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 25, No. 16, 22688, 03.07.2015, p. 3382-3389.

Research output: Contribution to journalArticle

Lim, SM, Xie, T, Westover, KD, Ficarro, SB, Tae, HS, Gurbani, D, Sim, T, Marto, JA, Jänne, PA, Crews, CM & Gray, NS 2015, 'Development of small molecules targeting the pseudokinase Her3', Bioorganic and Medicinal Chemistry Letters, vol. 25, no. 16, 22688, pp. 3382-3389. https://doi.org/10.1016/j.bmcl.2015.04.103
Lim SM, Xie T, Westover KD, Ficarro SB, Tae HS, Gurbani D et al. Development of small molecules targeting the pseudokinase Her3. Bioorganic and Medicinal Chemistry Letters. 2015 Jul 3;25(16):3382-3389. 22688. https://doi.org/10.1016/j.bmcl.2015.04.103
Lim, Sang Min ; Xie, Ting ; Westover, Kenneth D. ; Ficarro, Scott B. ; Tae, Hyun Seop ; Gurbani, Deepak ; Sim, Taebo ; Marto, Jarrod A. ; Jänne, Pasi A. ; Crews, Craig M. ; Gray, Nathanael S. / Development of small molecules targeting the pseudokinase Her3. In: Bioorganic and Medicinal Chemistry Letters. 2015 ; Vol. 25, No. 16. pp. 3382-3389.
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