title: Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors.
abstract: High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: rwurz@amgen.com.
authors: Ryan P
authors: RP
authors: Wurz
authors: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA. Electronic address: csastri@amgen.com.
authors: Christine
authors: C
authors: Sastri
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Derin C
authors: DC
authors: D'Amico
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Brad
authors: B
authors: Herberich
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Claire L M
authors: CLM
authors: Jackson
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Liping H
authors: LH
authors: Pettus
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Andrew S
authors: AS
authors: Tasker
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Bin
authors: B
authors: Wu
authors: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Nadia
authors: N
authors: Guerrero
authors: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: J Russell
authors: JR
authors: Lipford
authors: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Jeffrey T
authors: JT
authors: Winston
authors: Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Yajing
authors: Y
authors: Yang
authors: Department of Discovery Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Paul
authors: P
authors: Wang
authors: Department of Discovery Attribute Sciences, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Yen
authors: Y
authors: Nguyen
authors: Department of Molecular Engineering, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Kristin L
authors: KL
authors: Andrews
authors: Department of Molecular Engineering, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Xin
authors: X
authors: Huang
authors: Department of Molecular Engineering, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Matthew R
authors: MR
authors: Lee
authors: Department of Molecular Engineering, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Christopher
authors: C
authors: Mohr
authors: Department of Molecular Engineering, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: J D
authors: JD
authors: Zhang
authors: Department of Pre-pivotal Drug Product, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Darren L
authors: DL
authors: Reid
authors: Department of Clinical Pharmacology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Yang
authors: Y
authors: Xu
authors: Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Yihong
authors: Y
authors: Zhou
authors: Department of Therapeutic Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320-1799, USA.
authors: Hui-Ling
authors: HL
authors: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C490587:PIM2 protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011724:Pyridazines; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1
keywords: Hematologic cancer; Kinase inhibitor; Multiple myeloma; Oncology; Pim kinase; Proliferation