Abstract 5398: In vivo development of pan-Pim kinase small molecule inhibitors

Pim-1,-2, and -3 are constitutively active serine-threonine kinases which are partially redundant and regulate multiple pathways important for tumor growth and survival. One or more of the human Pims are over-expressed in multiple hematological tumor types (e.g. multiple myeloma (MM), NHL and AML) and in some solid tumors (e.g. prostate and SCLC). Pim over-expression correlates with malignancy and poor prognosis in several indications. Our goal was to generate a pan Pim kinase inhibitor with acceptable physical chemical properties and in vivo anti-tumor efficacy. Here we present data on two ATP-competitive, orally bioavailable pan Pim inhibitors, Compound I and Compound II. These inhibitors have potent enzymatic and cellular activity, acceptable pharmacokinetic properties (PK) and robust in vivo efficacy. In a kinase enzyme assay Compound I inhibits Pim-1 and Pim-2 activity with 0.4 nM and 0.7 nM IC50s, respectively, while Compound II is even more potent with Pim-1 and Pim-2 IC50s of 0.1 nM/0.1 nM. In a cellular assay which measures inhibition of the Pim downstream substrate phospho-BAD (p-BAD), compounds I and II demonstrate IC50s of 56 and 16 nM, respectively. In an in vivo pharmacodynamic assay (PD) to demonstrate on-target Pim activity, compounds I and II significantly inhibited p-BAD in KMS-12-BM multiple myeloma tumors for 16 hours post dose. Treatment of KMS-12-BM tumor xenografts with Compound I demonstrated robust in vivo anti-tumor efficacy resulting in 23% tumor regression at 50 mg/kg BID and tumor stasis at 100 mg/kg QD. Compound II demonstrated improved PK properties leading to greater anti-tumor efficacy of 33% tumor regression at 100 mg/kg QD and tumor stasis at 50 mg/kg QD. Compound II showed efficacy in an orthotopic model of multiple myeloma and in models of AML and DLBCL. Combination treatment of Compound II and the standard of care Dexamethasone in the multiple myeloma RPMI-8226 xenograft model demonstrated enhanced tumor growth inhibition compared to either single agent activity. In summary, Compound I and II are potent and selective inhibitors of Pim kinases with excellent in vivo properties. Pim kinase inhibitors, either as monotherapy or in combination with dexamethasone, may be effective clinical strategies for certain cancer patients. Citation Format: Bethany Mattson, Christine. E. Sastri, Nadia Guerrero, Dean Hickman, Jie Chen, Tian Wu, Hui-Ling Wang, Andrew Taskar, Brian Lanman, Anthony B. Reed, Jude Canon, J. Russell Lipford, Karen Rex. In vivo development of pan-Pim kinase small molecule inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5398. doi:10.1158/1538-7445.AM2015-5398