Hit to Lead Account of the Discovery of a New Class of Inhibitors of Pim Kinases and Crystallographic Studies Revealing an Unusual Kinase Binding Mode

Qian, Kevin; Wang, Lian; Cywin, Charles L.; Farmer, Bennett T.; Hickey, Eugene R.; Homon, Carol; Jakes, Scott; Kashem, Mohammed A.; Lee, George; Leonard, Scott F.; Li, Jun; Magboo, Ronald; Mao, Wang; Pack, Edward J.; Peng, Charlene; Prokopowicz, Anthony S.; Welzel, Morgan; Wolak, John P.; Morwick, Tina M.

doi:10.1021/jm801242y

Cited by 68 publications

(57 citation statements)

References 84 publications

(60 reference statements)

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“…These inhibitors include a series of pyrazine compounds (compound 9) as well as a series of isoxazolo [3,4-b]quinoline-3,4(1H,9H)-diones (compound 6). 131,132 Similar halogen hinge interactions have been reported for 4,5,6,7-tetrabromo-1H-benzimidazole, which also strongly inhibit CK2 and di-chloro-substituted β-carbolines (S Knapp, unpublished data, 2009 and pdb code: 3CXW). 133,134 An interesting aspect of many PIM inhibitors is the often observed selectivity of many inhibitors for PIM1 and PIM3 over PIM2, the latter usually being inhibited with much lower potency.…”

Section: -121supporting

confidence: 62%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

327

413

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The online version of this article has a Supplementary Appendix.The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. Haematologica 2010;95:1004-1015. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACTin blast crisis. 6 Abundant levels of PIM1 were found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFNγ, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels ( Figure 1). Other studies have shown that PIM1 kinase is significantly protected from proteasomal degradation by heat shock proteins (Hsp70, Hsp90). 8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression. 10,11 Germline inactivation of the PIM1 gene was associated with a mild phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1 -/-mice showed erythrocytic microcytosis and PIM1-/-B cells and bone marrow-derived mast c...

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Section: -121supporting

confidence: 62%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

327

413

View full text Add to dashboard Cite

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“…The detailed mechanisms of the interaction among Pim family members in HCC also need further study. In view of the important roles played by Pim-2 in tumorigenesis, researches about its inhibitors grow hotter [24]. Thiazolidine congeners and isoxazole homologues are the most popular ones [25,26].…”

Section: Discussionmentioning

confidence: 99%

Pim-2 Activates API-5 to Inhibit the Apoptosis of Hepatocellular Carcinoma Cells Through NF-κB Pathway

Kawaguchi

Zhang

Shi

et al. 2009

Pathol. Oncol. Res.

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Pim-2 is proved to be relevant to the tumorigenesis of hepatocellular carcinoma (HCC), but the mechanism is unclear. We studied the relationship among Pim-2, NF-kappaB and API-5. In our experiment, expression level of the three factors and phosphorylation level of API-5, as well as NF-kappaB activity, were detected in HCC tissues and the nontumorous controls. Then Pim-2 gene was transfected into nontumorous liver cells L02, and Pim-2 SiRNA was transfected into hepatoblastoma cell line HepG2. Parthenolide was added as NF-kappaB inhibitor. The same detections as above were repeated in the cells, along with the apoptosis analysis. We found the levels of Pim-2, NF-kappaB and API-5, as well as NF-kappaB activity, were significantly higher in HCC tissues. Pim-2 level was increased in L02 cells after the transfection of Pim-2 gene, but decreased in HepG2 cells after the transfection of Pim-2 SiRNA. The levels of NF-kappaB and API-5, as well as NF-kappaB activity and API-5 phosphorylation level, were in accordance with Pim-2 level, but could be reversed by Parthenolide. Cell apoptosis rates were negatively correlated with API-5 phosphorylation level. Therefore, we infer that Pim-2 could activate API-5 to inhibit the apoptosis of liver cells, and NF-kappaB is the key regulator.

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“…It was reported that Pim-2 inhibition was more difficult to achieve than Pim-1 and Pim-3, likely due to its low K m value for ATP. 15,20 The potencies of compounds against Pim-1 kinase were influenced by several factors such as carbon chain length of the aminoalkyl group, the types of substituent at amine, and the linker between aminoalkyl group and aminopyrimidine. Compound 6c with 3-(N,N-dimethylamino)propoxy and 6h with 3-(N,Ndiethylamino)propylamino were the most potent against Pim-1 kinase.…”

Section: 15-18mentioning

confidence: 99%

3,5-Bis(aminopyrimidinyl)indole Derivatives: Synthesis and Evaluation of Pim Kinase Inhibitory Activities

Lee

More²,

Yang³

et al. 2014

Bulletin of the Korean Chemical Society

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Pim kinases are promising targets in the treatment of hematopoietic and solid cancers. Meridianin C was chosen as a starting point to discover novel pim kinase inhibitors. Using known pim kinase's structural information, aminopyrimidine was introduced to provide the hydrogen-bonding interactions with the conserved lysine residue in the ATP binding pocket of all three Pim kinases. Synthesized 3,5-bis(aminopyrimidinyl)indole derivatives showed pan-pim inhibitory activity. Aminoalkyl substituent was attached on the aminopyrimidine to further enhance the potency and physicochemical properties of compound. The research reveals a significative way of designing compounds with high potency and kinase selectivity for pan-pim kinases.

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Hit to Lead Account of the Discovery of a New Class of Inhibitors of Pim Kinases and Crystallographic Studies Revealing an Unusual Kinase Binding Mode

Cited by 68 publications

References 84 publications

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Pim-2 Activates API-5 to Inhibit the Apoptosis of Hepatocellular Carcinoma Cells Through NF-κB Pathway

3,5-Bis(aminopyrimidinyl)indole Derivatives: Synthesis and Evaluation of Pim Kinase Inhibitory Activities

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