Novel Pan-Pim Kinase Inhibitors With Imidazopyridazine and Thiazolidinedione Structure Exert Potent Antitumor Activities.

Yuichi Sawaguchi,Hiroyuki Nishiyama,Ryuta Yamazaki,Yukiko Nishiyama,Tatsuya Ibuki,Masayuki Mae,Fukiko Nishisaka,Toshio Sasai,Takeshi Matsuzaki,Atsuhiro Abe

doi:10.3389/fphar.2021.672536

Yuichi Sawaguchi, Hiroyuki Nishiyama + Show 8 more

Open Access

https://doi.org/10.3389/fphar.2021.672536

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Abstract

Pim kinases are overexpressed in various types of hematological malignancies and solid carcinomas, and promote cell proliferation and survival. Here in this study, we investigated the preclinical profile of novel pan-Pim kinase inhibitors with imidazopyridazine and thiazolidinedione structure. Imidazopyridazine-thiazolidinediones inhibited activities of Pim kinases with IC50 values of tens to hundreds nanomolar. With YPC-21440 and/or YPC-21817, which exhibited especially high inhibitory activities against Pim kinases, we investigated in vitro and in vivo activities of imidazopyridazine-thiazolidinediones. In silico analysis of binding mode of YPC-21440 and Pim kinases revealed that it directly bound to ATP-binding pockets of Pim kinases. In the kinase panel tested, YPC-21440 and YPC-21817 were highly specific to Pim kinases. These compounds exerted antiproliferative activities against various cancer cell lines derived from hematological malignancies and solid carcinomas. Furthermore, they suppressed phosphorylation of Pim kinase substrates, arrested cell cycle at the G1 phase, and induced apoptosis in cultured cancer cells. In tumor xenograft models, YPC-21440 methanesulfonate and YPC-21817 methanesulfonate exerted antitumor activities. Furthermore, pharmacodynamic analysis with a xenograft model suggested that YPC-21817 methanesulfonate inhibited Pim kinases in tumors. In conclusion, our data revealed that imidazopyridazine-thiazolidinediones are novel Pim kinases inhibitors, effective on various types of cancer cell lines both in vitro and in vivo.

Highlights

Pim kinases are serine/threonine kinases and composed of three isoforms, Pim-1, 2, and 3, which are highly homologous to each other. They are overexpressed in hematological malignancies, such as acute myeloid leukemia (AML), and solid tumors, such as prostate, gastric, and colon cancer, and their expression is correlated with poor prognosis in these types of cancers (Dhanasekaran et al, 2001; Popinanova et al, 2007; Peng et al, 2013; Lou et al, 2014; Cheng et al, 2017)
YPC-21440 and YPC-21817 most potently inhibited Pim-1, 2, and 3, with IC50 values ranging from 0.012 to 0.11 μM. With these two compounds as representatives, we evaluated the pharmacological actions of imidazopyridazinethiazolidinediones
To investigate the specificity of imidazopyridazine-thiazolidinediones, we examined the inhibitory effects of YPC-21440 and YPC-21817 against tyrosine and serine/threonine kinase panels (Figure 2)

Summary

Introduction

Pim kinases are serine/threonine kinases and composed of three isoforms, Pim-1, 2, and 3, which are highly homologous to each other. Lack of significant toxicity in Pim-1, 2, and 3 tripleknockout mice suggests that their signaling network is not essential for functions of normal tissues (Mikkers et al, 2004). These reports imply that Pim kinase inhibitors are expected to exhibit cytotoxicity in cancer cells, but to contribute to overcoming chemoresistance and immunotherapy. Pim kinases are indicated to be complementary to each other in c-Myc-induced mice lymphoma models (van der Lugt et al, 1995; Mikkers et al, 2002), suggesting that activities of all Pim kinase isoforms should be inhibited in order to exert anticancer effects on cancers in which Pim kinase signaling contributes to malignancy

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