Evaluation of the antiproliferative effects of the HASPIN inhibitor CHR-6494 in breast cancer cell lines

Abstract

HASPIN is a serine/threonine kinase that regulates mitosis by phosphorylating histone H3 at threonine 3. The expression levels of HASPIN in various cancers are associated with tumor malignancy and poor survival, suggesting that HASPIN inhibition may suppress cancer growth. As HASPIN mRNA levels are elevated in human breast cancer tissues compared with adjacent normal tissues, we examined the growth-suppressive effects of CHR-6494, a potent HASPIN inhibitor, in breast cancer cell lines in vitro and in vivo. We found that HASPIN was expressed in breast cancer cells of all molecular subtypes, as well as in immortalized mammary epithelial cells. HASPIN expression levels appeared to be correlated with the cell growth rate but not the molecular subtype of breast cancer. CHR-6494 exhibited potent antiproliferative effects against breast cancer cell lines and immortalized mammary epithelial cells in vitro, but failed to inhibit the growth of MDA-MB-231 xenografted tumors under conditions that have significant effects in a colorectal cancer model. These results imply that CHR-6494 does have antiproliferative effects in some situations, and further drug screening efforts are anticipated to identify more potent and selective HASPIN inhibition for use as an anticancer agent in breast cancer patients.

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

“…Haspin and aurora B kinases phosphorylate histone H3 in mitotic progression [ 146 ]. Haspin inhibition with CHR-6494 impairs proliferation of breast cancer cell lines but have no effect on cell proliferation of breast cancer cell line xenographs [ 147 ]. Another haspin inhibitor, CX-6258 also impaired proliferation and generated the formation of micronuclei in melanoma cell lines [ 125 ].…”

Loss of haspin suppresses cancer cell proliferation by interfering with cell cycle progression at multiple stages

“…The other potent haspin inhibitor, CHR-6494, is an imidazolyl-pyridazine derivative and has shown antiproliferative activities in multiple cancers. 22,[26][27][28] Previously, we found that both 5-ITu and CHR6494 could delay the interphase progression in HeLa and U2OS cancer cell lines. 29 This study adopts the fluorescent ubiquitination-based cell cycle indicators (Fucci) system to examine how the loss of haspin functions would impact the entire cell cycle at a single-cell level.…”

“…These mitotic defects closely resemble the phenotypes observed from haspin gene depletion. The other potent haspin inhibitor, CHR‐6494, is an imidazolyl‐pyridazine derivative and has shown antiproliferative activities in multiple cancers 22,26–28 …”

N1‐Benzoylated 5‐(4‐pyridinyl)indazole‐based kinase inhibitors: Attaining haspin and Clk4 selectivity via modulation of the benzoyl substituents

“…It is highly upregulated in a variety of cancer cells such as Burkitt's lymphoma, chronic lymphocytic leukemias, bladder cancer, ovarian cancer, breast cancer and colorectal cancer. [ 10–13 ] Inhibition of haspin leads to improper arrangement and separation of sister chromatids during the cell division resulting in an arrest in G2/M phase and subsequently mitotic catastrophe leading to cell apoptosis. Hence, inhibitors targeting haspin exhibit strong antitumor effects.…”