Abstract
The high expression of proviral insertion site of Moloney murine leukemia virus kinases (Pim-1, -2, and -3) in cancers, particularly the hematopoietic malignancies, is believed to play a role in promoting cell survival and proliferation while suppressing apoptosis. The three isoforms of Pim protein appear largely redundant in their oncogenic functions. Thus, a pan-Pim kinase inhibitor is highly desirable. However, cell active pan-Pim inhibitors have proven difficult to develop because Pim-2 has a low Km for ATP and therefore requires a very potent inhibitor to effectively block the kinase activity at cellular ATP concentrations. Herein, we report a series of quinazolinone-pyrrolopyrrolones as potent and selective pan-Pim inhibitors. In particular, compound 17 is orally efficacious in a mouse xenograft model (KMS-12 BM) of multiple myeloma, with 93% tumor growth inhibition at 50 mg/kg QD upon oral dosing.
MeSH terms
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Administration, Oral
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug
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Drug Discovery*
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Humans
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Mice
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Models, Molecular
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-pim-1 / metabolism
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Pyrroles / administration & dosage
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Quinazolinones / administration & dosage
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Quinazolinones / chemistry
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Quinazolinones / pharmacology*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrroles
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Quinazolinones
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Proto-Oncogene Proteins c-pim-1
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proto-oncogene proteins pim