Abstract 1325: TPX-0022, a polypharmacology inhibitor of MET/CSF1R/SRC inhibits tumor growth by promoting anti-tumor immune responses
Authors: Deng Wei , Zhai Dayong , Rogers Evan , Zhang Xin , Lee Dong , Ung Jane , Zhang Han , Liu Jing , Lu Yuelie , Huang John , Graber Armin , Zimmerman Zach , Lim John , Whitten Jeffrey , Cui J. Jean 
Published: August 2019

Abstract
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 &lt;3 nM and cell growth with an IC50 of 14 nM. In addition, TPX-0022 effectively inhibited the growth of Ba/F3 ETV6-CSF1R xenograft tumors in vivo. In the CSF1/CSF1R signaling-dependent M-NFS-60 model, TPX-0022 not only exhibited potency with an IC50 of 0.3 nM under baseline condition, but also potently inhibited the growth of M-NFS-60 cells with an IC50 of 11.6 nM in the presence of exogenous CSF1 at 1 ng/mL concentration, a condition mimicking typical in vivo conditions in the presence of advanced tumors. In contrast, in our study, the potency of the type II CSF1R inhibitor PLX-3397 demonstrated a strong dependency on the concentration of mouse CSF1, as the anti-proliferation IC50 shifted from &lt;0.1 nM to 146.4 nM when CSF1 concentration changed from baseline to 1 ng/mL. Finally, in the MC38 syngeneic mouse model, TPX-0022 effectively reduced TAMs, altered the polarity of TAMs toward a more M1 phenotype, increased cytotoxic T cells and inhibited the growth of MC38 tumors. These preclinical results demonstrated a potent CSF1R inhibitory activity of TPX-0022 and the ability of TPX-0022 to inhibit tumor growth and promote a pro-inflammatory anti-tumor microenvironment.
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.