Targeting Haspin Kinase with SEL120: Advancing Colorectal Cancer Therapy through Single and Combined Inhibitory Approaches

The mitotic process is a well-established target for cancer drug therapies, with anti-mitotic drugs like vinca alkaloids and taxanes being prominent in chemotherapy. However, these drugs can have adverse side effects, including neurological and hematological toxicities. There is a significant interest in finding new drug targets in mitosis to develop safer and more effective cancer treatments. Haspin, a kinase implicated in mitosis, has emerged as a potential target, and its inhibition offers a new strategy in anti-mitotic cancer therapy.

This research introduces SEL120, a newly developed ATP competitive inhibitor of Haspin kinase, which exhibits low nanomolar binding affinities. SEL120 has demonstrated the ability to inhibit the proliferation and clonogenic survival of various tumor cell lines, particularly in colon, lung (NSCLC), and B cell lymphoma cell lines.

The primary substrate of Haspin is histone H3, which Haspin phosphorylates at threonine T3 during mitosis. Utilizing siRNA, the study confirmed that the phosphorylation at this site can be fully suppressed by Haspin knockdown in colon and lung cancer cell lines. Additionally, treatment with SEL120 resulted in decreased phosphorylation of histone H3 (Thr3) in both synchronized and asynchronous cell lines. Cells depleted of Haspin were found to arrest in prometaphase due to chromosome alignment issues and activation of the mitotic checkpoint. Treatment with SEL120 induced mitotic cell cycle arrest in the HCT116 and A549 cell lines, confirming the inhibition of Haspin as the mechanism of action. The co-administration of SEL120 with an AuroraB inhibitor, AZD1152, led to synergistic cytostatic effects, increasing the number of cells arrested in mitosis without the polyploidy typically associated with AuroraB inhibition.

In vivo studies with oral administration of SEL120 showed significant anti-tumor efficacy in the HCT116 xenograft model, with tumor growth inhibition exceeding 80%. Pharmacokinetic, ADMET, and histopathological analyses provided promising results for the development of new therapeutics from the SEL120 program. The data presented supports Haspin as a potential target for anti-cancer treatments, especially for colon, lung, and lymphoma cancers.