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Aberrant activation of the HGF/MET pathway has frequently been found in human cancers via MET mutation, gene amplification and translocation, as well as HGF paracrine or autocrine upregulation. The abnormal HGF/MET signaling not only acts as an oncogenic driver but also confers resistance to many cancer therapies, such as EGFR targeted therapy in NSCLC. One key downstream effector for activated MET is SRC, which is also involved in malignancy formation, tumor metastasis and drug resistance. In the tumor microenvironment, CSF1R plays an important role in regulation of tumor associated macrophages, which promote tumor progression and angiogenesis. Therefore, the polypharmacological inhibition of MET/SRC/CSF1R has great potential for more effectively targeting cancers with abnormal HGF/MET signaling via targeting both tumor intrinsic signaling and the tumor microenvironment. TPX-0022, a novel macrocyclic compound, has been designed and optimized to inhibit MET/CSF1R/SRC with enzymatic kinase inhibition IC50s of 0.14, 0.76 and 0.12 nM, respectively. TPX-0022 potently inhibited cell proliferation of the MET-amplified MKN-45 and SNU-5 gastric cancer cells, with IC50s Citation Format: Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Dong Lee, Jane Ung, Han Zhang, Jing Liu, Yuelie Lu, John Huang, Armin Graber, Zach Zimmerman, John Lim, Jeffrey Whitten, J. Jean Cui. TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1321.

In the tumor microenvironment, tumor associated macrophages (TAMs) support tumor growth by suppressing antitumor immune responses and promoting angiogenesis, which is associated with disease progression and poor clinical outcomes. In contrast to the classic phagocytic and cytotoxic pro-inflammatory M1 phenotype of macrophages engulfing and digesting pathogens, TAMs often adopt the anti-inflammatory and immune regulatory M2 phenotype in response to colony stimulating factor 1 (CSF1), which is produced by either tumor cells or stroma cells. Signaling through colony stimulating factor 1 receptor (CSF1R), a receptor tyrosine kinase expressed on the surface of mononuclear phagocytes, is involved in the recruitment of TAMs and has been associated with tumor progression and suppression of the immune response. Thus, CSF1R represents a key therapeutic target. TPX-0022, a type I kinase inhibitor with a novel macrocyclic structure, has been designed and optimized to inhibit MET/CSF1R/SRC with enzymatic kinase inhibition IC50s of 0.14, 0.76 and 0.12 nM, respectively. In a Ba/F3 ETV6-CSF1R cell model, TPX-0022 inhibited both autophosphorylation of CSF1R with an IC50 Citation Format: Wei Deng, Dayong Zhai, Evan Rogers, Xin Zhang, Dong Lee, Jane Ung, Han Zhang, Jing Liu, Yuelie Lu, John Huang, Armin Graber, Zach Zimmerman, John Lim, Jeffrey Whitten, J. Jean Cui. TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC inhibits tumor growth by promoting anti-tumor immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1325.