Development of small molecules targeting the pseudokinase Her3

• Published in: Bioorganic & medicinal chemistry letters Vol. 25; no. 16; pp. 3382 - 3389
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.08.2015; Elsevier
• Subjects: Acrylamides - chemical synthesis; Acrylamides - chemistry; Acrylamides - pharmacology; Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - chemistry; Adenine - pharmacology; Cancer; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Delivery Systems; Drug Screening Assays, Antitumor; Her3; Humans; Hydrophobic tagging; Inhibitory Concentration 50; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Pseudokinase; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrazolopyrimidine; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Receptor, ErbB-3 - antagonists & inhibitors; Science & Technology; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Hydrophobic tagging; Pseudokinase; Pyrazolopyrimidine; Her3; Cancer; DOMAIN; PROTEIN; TYROSINE KINASE; DISCOVERY; LUNG-CANCER; POTENT; ERBB3; SELECTIVE INHIBITORS; DEGRADATION; EXTENDED 5-SUBSTITUENT
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2015.04.103

[Display omitted] 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.