Development of small molecules targeting the pseudokinase Her3

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Her3 (human epidermal growth factor receptor 3) is a pseudokinase frequently dysregulated in various human cancers.
• Its lack of significant kinase activity has historically hindered small-molecule inhibitor development.
• Targeting Her3 is crucial for novel cancer therapy strategies.

Purpose of the Study:

• To report on the structure-based medicinal chemistry efforts leading to the discovery of novel Her3 inhibitors.
• To introduce the first selective irreversible Her3 ligand, TX1-85-1.
• To present a bifunctional compound, TX2-121-1, for inhibiting Her3-dependent signaling and growth.

Main Methods:

• Structure-based drug design and medicinal chemistry.
• Development of selective irreversible ligands targeting Her3's unique cysteine 721.
• Synthesis and characterization of bifunctional compounds incorporating specific moieties.

Main Results:

• Discovery of TX1-85-1, the first selective irreversible Her3 ligand, forming a covalent bond at cysteine 721.
• Development of TX2-121-1, a bifunctional compound inhibiting Her3 signaling and cancer cell growth.
• Successful structure-based optimization yielding potent and selective Her3 inhibitors.

Conclusions:

• The developed compounds represent a significant advancement in targeting Her3.
• These novel inhibitors offer potential for new therapeutic strategies in Her3-driven cancers.
• Structure-based design is effective for developing inhibitors against challenging targets like pseudokinases.