Abstract 3845: Antitumor activity of SEL120: An orally available dual inhibitors of Haspin/CDK9, for standalone and combination therapy with AuroraB inhibitors in solid tumors and hematopoietic malignancies
Authors: Rzymski Tomasz , Zarebski Adrian , Windak Renata , Sibinska Zaneta , Klosowska-Wardega Agnieszka , Trebacz Ewa , Cholody Marek , Szamborska-Gbur Agnieszka , Milik Mariusz , Prymula Katarzyna , Brzozka Krzysztof , Beuzen Nicolas 
Published: August 2012

The mitotic machinery is a validated target for potential drug therapies in cancer. However, anti-mitotic agents are not without complications from various side effects, notably neurological and hematological toxicities. There is much interest in identifying new drug targets in mitosis which could lead to safer and more efficacious treatments of cancer. Recently, Haspin has been identified as another important kinase involved in mitosis. Similar to other mitotic kinases such as Polo-like kinase-1 and the Aurora kinases, inhibition of Haspin represents a novel approach in anti-mitotic cancer therapeutics. In this study we report the development of SEL120, series of novel ATP competitive inhibitors of Haspin kinase. These compounds have binding affinities towards Haspin kinase in the low nM range. Several compounds in the series exerted significant activity on CDK9 (selectively over other CDK kinases), a part of positive transcription elongation factor b (P-TEFb) involved in the expression of survival proteins during progression of cancer. SEL120 inhibited proliferation and clonogenic survival of a number of tumor cell lines with particularly good cytostatic activity in colon, lung (NSCLS) and B cell lymphoma cell lines. The only substrate of Haspin reported in literature to date is histone H3. During mitosis Haspin targets a single site in this protein, namely threonine at position T3 (H3T3ph). By using siRNA, we have confirmed that Thr3 phosphorylation of histone H3 could be completely repressed by the knockdown of Haspin in HCT116 colon and A549 (NSCLC) lung cancer cell lines. We also consistently observed decreased phosphorylation of histone H3 (Thr3) in both synchronized and asynchronous cell lines treated with SEL120 inhibitor. In addition SEL120-1 treatment decreased levels of CDK9 biomarkers- phosphorylation of pol II CTD (Ser2) and expression of the pro-survival protein Mcl-1 Treatment with SEL120 consistently resulted in mitotic cell cycle arrest in A549 cell line confirming inhibition of Haspin as the mechanism of action. Remarkably, inhibitory activity on CDK9 correlated with levels of cell death. Furthermore, co-administration of SEL120 with an AuroraB inhibitors, resulted in strong synergistic cytostatic effects. Treatment with both compounds increased the number of cells arrested in mitosis, notably without any signs of polyploidy typically observed after inhibition of AuroraB. Oral administration of SEL120 (25mg/kg BID) revealed excellent potency in colon and B-cell lymphoma xenograft models. Analysis of pharamcokinetic, ADMET and histopathological parameters afforded encouraging results towards potential development of new therapeutics emerging from our SEL120 program.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3845. doi:1538-7445.AM2012-3845