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Structure Guided Optimization, In Vitro Activity and In Vivo Activity of Pan-PIM Kinase Inhibitors

Burger, Matthew and Han, Wooseok and Lan, Jiong and Nishiguchi, Gisele and Bellamacina, Cornelia and Lindvall, Mika and Atallah, Gordana and Ding, Yu and Mathur, Michelle and Mcbride, Christopher and Mieuli, Elizabeth and Muller, Kristine and Tamez Jr., Victoriano and Zhang, Yanchen and Huh, Kay and Feucht, Paul and Zavorotinskaya, Tatiana and Dai, Yumin and Holash, Jocelyn and Langowski, John and Garcia, Pablo (2013) Structure Guided Optimization, In Vitro Activity and In Vivo Activity of Pan-PIM Kinase Inhibitors. American Chemical Society Medicinal Chemistry Letters, 4 (12). pp. 1193-1197.

Abstract

Proviral Insertion of Moloney virus (PIM) 1, 2 and 3 kinases are serine/threonine kinases that normally function in survival and proliferation of hematopoietic cells. High expression of PIM1, 2 & 3 is frequently observed in many human malignancies, including multiple myeloma, non-Hodgkins lymphoma, and myeloid leukemias. As such, there is interest in determining whether selective PIM inhibition can improve outcomes of these human cancers. Herein, we describe our efforts towards this goal. The structure guided optimization of a singleton high throughput screening hit in which the potency against all three PIM isoforms was increased >10,000 fold to yield compounds with pan PIM Ki’s < 10 picoM is described. During the optimization, a focus was initially placed on increasing potency while simultaneously reducing the liphophilicity and then, from a low logP space, a hydrophobic interaction was optimized. From these efforts, compound 5d was identified with suitable PK properties and kinase selectivity to establish a PK/PD-efficacy relationship in multiple myeloma and acute myeloid leukemia Pim dependent tumor models.

Item Type: Article
Keywords: Proviral Insetion Site in Moloney Murine Leukemia Virus kinases inhibitors, Pim1 kinase inhibitor, Pim2 kinase inhibitor, Pim3 kinase inhibitor, pan-Pim kinase inhibitors
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/9729

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