Data from A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth <i>In vitro</i> and <i>In vivo</i>

• DOI: 10.1158/1535-7163.c.6531675.v1
• Publication Date: 2023-04-01T06:07:38Z
• Authors: Kuzhuvelil B. Har...; Ajaikumar B. Kunn...; Nobuo Ochi; Zhimin Tong; Amit Deorukhkar; Bokyung Sung; Lloyd Kelland; Stephen Jamieson; Rachel Sutherland; Tony Raynham; Mark Charles; Azadeh Bagherzadeh; Caroline Foxton; Alexandra Boakes; Muddasar Farooq; Dipen Maru; Parmeswaran Diaga...; Yoichi Matsuo; James Sinnett-Smith; Juri Gelovani; Sunil Krishnan; Bharat B. Aggarwal; Enrique Rozengurt; Christopher R. Ir...; Sushovan Guha

&lt;div&gt;Abstract&lt;p&gt;Protein kinase D (PKD) family members are increasingly implicated in multiple normal and abnormal biological functions, including signaling pathways that promote mitogenesis pancreatic cancer. However, nothing is known about the effects of targeting PKD Our inhibitor discovery program identified CRT0066101 as a specific all isoforms. The aim our study was to determine Initially, we showed autophosphorylated PKD1 PKD2 (activated PKD1/2) significantly upregulated cancer PKD1/2 expressed cell lines. Using Panc-1 model system, reduced bromodeoxyuridine incorporation; increased apoptosis; blocked neurotensin-induced activation; neurotensin-induced, PKD-mediated Hsp27 phosphorylation; attenuated PKD1-mediated NF-κB abrogated expression NF-κB-dependent proliferative prosurvival proteins. We given orally (80 mg/kg/d) for 24 days growth subcutaneous xenograft model. Activated treated tumor explants inhibited with peak concentration (12 μmol/L) achieved within 2 hours after oral administration. Further, 21 orthotopic potently &lt;i&gt;in vivo&lt;/i&gt;. Ki-67–positive proliferation index (&lt;i&gt;P&lt;/i&gt; &lt; 0.01), terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling–positive apoptotic cells 0.05), NF-κB–dependent proteins cyclin D1, survivin, cIAP-1. results show &lt;i&gt;for first time&lt;/i&gt; PKD-specific small-molecule blocks vivo&lt;/i&gt; novel therapeutic target Mol Cancer Ther; 9(5); 1136–46. ©2010 AACR.&lt;/p&gt;&lt;/div&gt;