Novel, isoform-selective, cholecystokinin A receptor antagonist inhibits colon and pancreatic cancers in preclinical models through novel mechanism of action

Abstract

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.

Cholecystokinin Antagonists: Fluorinated 5-Hydroxy-5-Aryl-Pyrrol-2-Ones as Experimental Agents for Brain, Colon and Pancreatic Cancer

“…Both agents inhibited tumour growth significantly from the day treatment was initiated and maintained the growth inhibitory properties until sacrifice ( Figure 10) Overall, it was clearly shown, that colon and pancreatic cancers response to CCK 1 antagonists and not CCK 2 antagonists [29]. We agree, it is unlikely that, gastrin is more important in pancreatic cancer than cholecystokinin.…”

“…Overall, the introduction of alkyl groups, most preferred an isobutyl-group, provided a CCK 1 selective antagonist a hydroxylpyrrolone 9, which was the selected development candidate PNB-028 for colon and pancreatic cancer associated with the CCK C receptor [29].…”

“…Initial results for CCK antagonists of the pyrrolone scaffold were communicated in the area of cancer therapeutics [27] and inflammation [28]. Here, a full biological evaluation of the cancer duo PNB-028 & PNB-291 will be reported in detail with respect to their antineoplastic properties [29].…”

N‒substituted 5‒hydroxy‒pyrrol‒2‒ones based cholecystokinin‒2 antagonists as experimental anticancer agents for the treatment of lung cancer

“…MAC16 is resistant to alkylating agents and has a high expression of the CCK receptor In line with the receptor expression, activity was found for lactame 7 and 9, but the IC 50 for benzylated lactame. 32,33 19 was 4 times higher. Previously we reported activity for lactame 9 on pancreatic cancer cell lines.…”

From Merck's CCK- Antagonists Via 4-Amino-2(5H)- Furanones towards 5-Hydroxy-Pyrrol-2-Ones: Design, Synthesis and Evaluation of PNB-001 & PNB-081 as Experimental Therapeutic Agents in Pain Management

“…Overall, the introduction of alkyl groups, most preferred an isobutylgroup, provided a CCK 1 selective antagonist PNB-081, which was the selected development candidate. A fluorinated analogue had potent anticancer properties via the CCKC receptor [38]. The phenyl-ethyl hydroxyl-pyrolone, lactam20=PNB-001 is CCK 2 / gastrin selective antagonist, outlined in (Figure 2).…”