title: Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action.
abstract: Colon and pancreatic cancers contribute to 90,000 deaths each year in the USA. These cancers lack targeted therapeutics due to heterogeneity of the disease and multiple causative factors. One important factor that contributes to increased colon and pancreatic cancer risk is gastrin. Gastrin mediates its actions through two G-protein coupled receptors (GPCRs): cholecystokinin receptor A (CCK-A) and CCK-B/gastrin receptor. Previous studies have indicated that colon cancer predominantly expresses CCK-A and responds to CCK-A isoform antagonists. However, many CCK-A antagonists have failed in the clinic due to poor pharmacokinetic properties or lack of efficacy. In the present study, we synthesized a library of CCK-A isoform-selective antagonists and tested them in various colon and pancreatic cancer preclinical models. The lead CCK-A isoform, selective antagonist PNB-028, bound to CCK-A at 12 nM with a 60-fold selectivity towards CCK-A over CCK-B. Furthermore, it inhibited the proliferation of CCK-A-expressing colon and pancreatic cancer cells without affecting the proliferation of non-cancerous cells. PNB-028 was also extremely effective in inhibiting the growth of MAC-16 and LoVo colon cancer and MIA PaCa pancreatic cancer xenografts in immune-compromised mice. Genome‑wide microarray and kinase-array studies indicate that PNB-028 inhibited oncogenic kinases and angiogenic factors to inhibit the growth of colon cancer xenografts. Safety pharmacology and toxicology studies have indicated that PNB-028 is extremely safe and has a wide safety margin. These studies suggest that targeting CCK-A selectively renders promise to treat colon and pancreatic cancers and that PNB-028 could become the next-generation treatment option.
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Suriyan
authors.initials: S
authors.lastname: Ponnusamy
authors.affiliation: Division of Pharmacy, School of Life and Health Sciences, Aston University, Birmingham, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Lattmann
authors.affiliation: PNB Vesper Life Sciences, Kerala, India.
authors.forename: Pornthip
authors.initials: P
authors.lastname: Lattmann
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Thirumagal
authors.initials: T
authors.lastname: Thiyagarajan
authors.affiliation: PNB Vesper Life Sciences, Kerala, India.
authors.forename: Balaram N
authors.initials: BN
authors.lastname: Padinjarethalakal
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Narayanan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000494:pharmacology; D019556:COS Cells; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019151:Peptide Library; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D043886:Receptor, Cholecystokinin A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D043886:Receptor, Cholecystokinin A