Reference Detail

Ref Type

PMID

Authors

Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Dong Lee, Jane Ung, Han Zhang, Jing Liu, YuelieLu, John Huang, Armin Graber, Zach Zimmerman, John Lim, Jeffrey Whitten, J. Jean Cui

Title

TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC for treatment of cancers with abnormal HGF/MET signaling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Proceedings of the American Association for Cancer Research			Mar 2019

URL

https://aacrjournals.org/cancerres/article/79/13_Supplement/1321/633458/Abstract-1321-TPX-0022-a-polypharmacology

Abstract Text

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 <0.2 nM, which ranked TPX-0022 as one of the most potent MET inhibitors. TPX-0022 caused suppression of MET auto-phosphorylation at an IC50 of approximately 0.3 nM in MKN-45 cell line. TPX-0022 also potently inhibited the phosphorylation of MET downstream signaling effectors, including AKT, ERK, STAT3 and PLCγ2 in a dose-dependent manner. In the cancer cell line- and patient-derived xenograft tumor models from gastric, lung and liver cancers harboring MET amplification or MET exon14 skipping mutations, TPX-0022 caused dramatic tumor regression and tumor growth inhibition, without overt abnormality and body weight loss in treated mice. Furthermore, the tumor inhibitory effect was associated with drastic inhibition of MET activity. Overall, TPX-0022 is a novel and potent MET inhibitor and has demonstrated desirable drug-like properties, a good preclinical safety profiles, that warrants further clinical development and an IND submission is currently planned.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
TPX-0022	TPX-0022	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
TPX-0022		TPX0022\|TPX 0022\|elzovantinib	CSF1R Inhibitor 28 MET Inhibitor 59 SRC Inhibitor 31	TPX-0022 inhibits Met, Csf1r, and Src, which may lead to growth inhibition in tumor cells (Proceedings of the American Association for Cancer Research, Vol 60, Mar 2019, Abstract #1321).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References