Insights from Pim1 structure for anti-cancer drug design

Ogawa, Naoko; Yuki, Hitomi; Tanaka, Akiko

doi:10.1517/17460441.2012.727394

Cited by 19 publications

(11 citation statements)

References 94 publications

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“…Our co-crystallography data revealed that 2′-HCA binds at the unique hinge region of Pim-1. This underscores the possibility of developing an effective therapeutic agent with high specificity for Pim-1 (39). …”

Section: Discussionmentioning

confidence: 90%

“…To determine how 2′-HCA specifically targets Pim-1, we used structural biology approaches. Pim-1 is functionally and structurally different from other classes of kinases (39), and has a unique hinge region sequence as well as novel hinge architecture (40). Our co-crystallography data revealed that 2′-HCA binds at the unique hinge region of Pim-1.…”

Section: Discussionmentioning

confidence: 99%

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A Novel Cinnamon-Related Natural Product with Pim-1 Inhibitory Activity Inhibits Leukemia and Skin Cancer

et al. 2015

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The Pim-1 kinase regulates cell survival, proliferation and differentiation and is overexpressed frequently in many malignancies including leukemia and skin cancer. In this study, we used kinase profiling analysis to demonstrate that 2′-hydroxycinnamicadelhyde (2′-HCA), a compound found in cinnamon, specifically inhibits Pim-1. Co-crystallography studies determined the hydrogen bonding pattern between 2′-HCA and Pim-1. Notably, 2′-HCA binding altered the apo kinase structure in a manner that shielded the ligand from solvent, thereby acting as a gatekeeper loop. Biologically, 2′-HCA inhibited the growth of human erythroleukemia or squamous epidermoid carcinoma cells by inducing apoptosis. The compound was also effective as a chemopreventive agent against EGF-mediated neoplastic transformation. Lastly, 2′-HCA potently suppressed the growth of mouse xenografts representing human leukemia or skin cancer. Overall, our results offered preclinical proof of concept for 2′-HCA as a potent anticancer principle arising from direct targeting of the Pim-1 kinase.

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Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

A Novel Cinnamon-Related Natural Product with Pim-1 Inhibitory Activity Inhibits Leukemia and Skin Cancer

et al. 2015

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“…Despite this, structurally diverse small‐molecule inhibitors have continued to be developed for regulation of Pim kinase activity both as research tools and drug candidates 2e. 3, 4 More than 400 small‐molecular Pim‐1 inhibitors with K i (IC 50 ) values <10 μ M have been registered in the ChEMBL database 3…”

Section: Methodsmentioning

confidence: 99%

“…Other kinases additionally form a hydrogen bond between the N1 atom of adenine and the backbone NH of the third hinge residue. The proline residue at position 123 in Pim‐1 precludes the kinase from this capability 3. In the present study, this distinctness in the protein structure was used for the construction of selective bisubstrate inhibitors, ARC(PIM) compounds.…”

Section: Methodsmentioning

confidence: 99%

Cover Picture: Modulable and Highly Diastereoselective Carbometalations of Cyclopropenes (Chem. Eur. J. 4/2014)

Didier

Delaye

Simaan

et al. 2014

Chemistry A European J

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“…All the above-mentioned compound classes showed acceptable IC 50 values toward Pim kinases (below 10 nmol/L in some cases, see Table 1). The ATP-binding pocket, along with the substrate-recognition residues are identified as crucial for Pim kinase inhibitors (19).…”

Section: Introductionmentioning

confidence: 99%

A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward Acute Myeloid Leukemia

Bjørnstad

Bruserud

Brenner

et al. 2019

Molecular Cancer Therapeutics

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More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo [2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine, or pyrrolo[2,3-g]indazole. The compounds were inhibitors of Pim kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC 50 below 5 mmol/L, and was 10 times less potent against nonmalignant cells. It perturbed Pim-kinase-mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity toward patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in preclinical animal models for AML.

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Insights from Pim1 structure for anti-cancer drug design

Cited by 19 publications

References 94 publications

A Novel Cinnamon-Related Natural Product with Pim-1 Inhibitory Activity Inhibits Leukemia and Skin Cancer

A Novel Cinnamon-Related Natural Product with Pim-1 Inhibitory Activity Inhibits Leukemia and Skin Cancer

Cover Picture: Modulable and Highly Diastereoselective Carbometalations of Cyclopropenes (Chem. Eur. J. 4/2014)

A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward Acute Myeloid Leukemia

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