PNB-028

PNB-028 for the Treatment of Pancreatic & Colon Cancers

Background about target
World Cancer Fact Sheets in 2008
(http://publications.cancerresearchuk.org/downloads/Product/CS_FS_WORLD_A4.pdf) indicated that GI cancers affect approximately 3.2 million people worldwide with an annual mortality of 0.6 million. In addition, a WHO report published on 6th February 2014 indicated that worldwide cancer incidence in the developing World will grow exponentially and will be cataclysmic if uncontrolled. The top cancers that have been forecasted to grow are pancreatic and gastric cancers, mediated by CCK receptors. Unfortunately, there is currently no targeted therapeutics available for these cancers, making them unmet medical needs. Patients suffering from these cancers undergo chemotherapy and radiation therapy, resulting in tremendous side effects. Hence, PNB-028 will potentially become the first targeted therapy for pancreatic cancer.
PNB-028 is a CCK-C isoform-selective antagonist acting on the CCK3a receptor according to the most recent literature. It binds to the extracellular loop on the cholecystokinin receptor.

In cell-based functional assays, PNB-028 inhibited the functions of CCK irreversibly in the nanomolar range. PNB-028 is the first irreversible CCK-C antagonist, required for the treatment of antineoplastic diseases.
PNB-028 was tested in nude mice colon and pancreatic cancer xenograft models. PNB-028 completely inhibited the growth of chemo-resistant MAC16 colon cancer tumour growth and MIAPACA pancreatic cancer tumour growth. While tumours in vehicle-treated animals metastasized to the lungs, tumours of PNB-028-treated animals were organ-confined. Vehicle-treated tumour-bearing animals lost weight and were cachectic, while the bodyweight of PNB-028-treated animals was within the acceptable range and was not cachectic. Interestingly, PNB-028-treated tumours demonstrated a significant reduction in various oncogenic kinases such as RSK, MAPK, and others, while phosphorylation of proteins such as p53 was increased. Moreover, histology studies demonstrated that tumours that were exposed to PNB-028 had a lower proliferation index as measured by Ki67.

PNB-028 was further screened in six colon cancer cell lines. Interestingly, all colon cancer cell lines expressed CCK receptors. PNB-028 significantly and robustly inhibited the growth of these colon cancer cell lines without affecting the growth of any normal non-cancerous cell lines. These results convincingly demonstrate the targeted nature of PNB-028 in inhibiting colon and pancreatic cancers.

Preclinical development studies: DMPK studies with PNB-028 indicated that PNB-028 was highly stable in rat, dog, and human liver microsomes. After 60 minutes of incubation, greater than 50, 50, and 90%, in rats, dogs, and humans, respectively, of PNB-028 still remained intact, indicating its high stability. In addition, PNB-028 was highly available in rats with a per cent bioavailability of close to 100% and an AUC of more than 1 µg h/ml. Other studies, including CaCo2 permeability and plasma protein binding, demonstrated favourable druggable properties of PNB-028. These studies were repeated twice to confirm the results.

Synthetic chemistry: PNB-028 synthetic scheme has only two steps and involves highly economical raw materials. PNB-028 was successfully synthesized on a large scale with purity exceeding 99%. Five kilograms of PNB-028 were synthesized to conduct regulatory toxicology and safety pharmacology studies.

Ongoing studies: Preclinical toxicology and safety pharmacology regulatory studies in accordance with ICH guidelines are currently ongoing. Formulation studies to determine the physic-chemical properties of PNB-028 are also ongoing.
The intellectual property of PNB-028 and structurally related molecules are well protected with patents filed in the US, Europe, and the rest of the World. A PCT application was also filed concurrently. Examination by the PTO office in Washington DC did not find any infringement issues with this series of molecules. USPTO has issued the patent on December 28, 2014.