1. Pharmacological targeting of the pseudokinase Her3
Ting Xie, Pasi A Jänne, Craig M Crews, Nathanael S Gray, Jarrod A Marto, Deepak Gurbani, Dalia Ercan, Hyun Seop Tae, Scott B Ficarro, Durga Udayakumar, Kenneth D Westover, Taebo Sim, Michael E Dodge, Steven M Riddle, Sang Min Lim Nat Chem Biol . 2014 Dec;10(12):1006-12. doi: 10.1038/nchembio.1658.
Her3 (also known as ErbB3) belongs to the epidermal growth factor receptor tyrosine kinases and is well credentialed as an anti-cancer target but is thought to be 'undruggable' using ATP-competitive small molecules because it lacks appreciable kinase activity. Here we report what is to our knowledge the first selective Her3 ligand, TX1-85-1, that forms a covalent bond with Cys721 located in the ATP-binding site of Her3. We demonstrate that covalent modification of Her3 inhibits Her3 signaling but not proliferation in some Her3-dependent cancer cell lines. Subsequent derivatization with a hydrophobic adamantane moiety demonstrates that the resultant bivalent ligand (TX2-121-1) enhances inhibition of Her3-dependent signaling. Treatment of cells with TX2-121-1 results in partial degradation of Her3 and serendipitously interferes with productive heterodimerization between Her3 with either Her2 or c-Met. These results suggest that small molecules will be capable of perturbing the biological function of Her3 and ~60 other pseudokinases found in human cells.
2. The significance of ErbB2/3 in the conversion of induced pluripotent stem cells into cancer stem cells
Masaharu Seno, Maram H Zahra, Ghmkin Hassan, Akimasa Seno Sci Rep . 2022 Feb 17;12(1):2711. doi: 10.1038/s41598-022-04980-y.
Cancer stem cells (CSCs) are suggested to be responsible for drug resistance and aggressive phenotypes of tumors. Mechanisms of CSC induction are still under investigation. Our lab has established a novel method to generate CSCs from iPSCs under a cancerous microenvironment mimicked by the conditioned medium (CM) of cancer-derived cells. Here, we analyzed the transcriptome of CSCs, which were converted from iPSCs with CM from pancreatic ductal adenocarcinoma cells. The differentially expressed genes were identified and used to explore pathway enrichment. From the comparison of the CSCs with iPSCs, genes with elevated expression were related to the ErbB2/3 signaling pathway. Inhibition of either ErbB2 with lapatinib as a tyrosine kinase inhibitor or ErbB3 with TX1-85-1 or siRNAs arrested cell proliferation, inhibited the in vitro tumorigenicity, and lead to loss of stemness in the converting cells. The self-renewal and tube formation abilities of cells were also abolished while CD24 and Oct3/4 levels were reduced, and the MAPK pathway was overactivated. This study shows a potential involvement of the ErbB2/ErbB3 pathway in CSC generation and could lead to new insight into the mechanism of tumorigenesis and the way of cancer prevention.
3. Development of small molecules targeting the pseudokinase Her3
Pasi A Jänne, Craig M Crews, Nathanael S Gray, Jarrod A Marto, Deepak Gurbani, Scott B Ficarro, Hyun Seop Tae, Kenneth D Westover, Taebo Sim, Sang Min Lim, Ting Xie Bioorg Med Chem Lett . 2015 Aug 15;25(16):3382-9. doi: 10.1016/j.bmcl.2015.04.103.
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.
