PNB 291

PNB-291 for the Treatment of Brain and Lung Cancers

Background about target Relevance and need for new medicines is well described on the cancer research uk web site (http://www.cancerresearchuk.org/about-cancer/type/secondary-cancers/secondary-brain-tumours/secondary-brain-tumours) One chemotherapeutic option for brain cancer is the treatment with temozolomide, which was developed by Aston University. In brain cancer mengionomas express CCK1 receptors and astrocytomas CCK2 receptors, explaining, why in vitro mixed CCK antagonists are most efficient in inhibiting cell proliferation. The occurrence of brain tumours is increasing steadily and chemotherapy is the treatment of choice due to the protected location of the brain. Cis-platin-based drugs are first-line treatment for colon/lung cancer and in a reported study and confirmed by our own studies, in the presence of a CCK antagonist, only a ¼ of the dose of Pt drug is required for the same anticancer effect.

Preclinical studies: PNB-291 is a non-selective mixed CCK antagonist, inhibiting the effects of gastrin and cholecystokinin. The molecular target is binding to the third extracellular loop on the gastrin receptor. In line with binding studies, in cell-based assays, PNB-291 inhibited the U373MG brain cancer cell line in the low nM concentrations. PNB-291 was found 21 times better than the L-365,260, the Merck standard and 100 times better than devazepide. Selective antagonists only show a partial response, as both pathways need to be blocked to achieve maximum efficacy. PNB-291 was tested in a xenograft study using the human U87 cancer cell line. After 30 days in nude mice the size of the tumour volume was approximately reduced to a third compared to the control and the effect was found to be dose-dependent. Most interestingly, the response rate was 100% and the route of administration was via PO. PNB-291 is a more potent version of PNB-091 in terms of binding affinity, in vitro cell-based activity and in vivo efficacy assessed here in the MAC-16 tumour model. The increase in in-vivo activity may be based on a higher oral bioavailability. Using the MAC16 allograft model for a 30 mg/kg dose close to 90% inhibition was achieved, resulting in a human equivalent dose of 200 mg, which is easily formulated in a hard gelatin capsule. PNB-091 and PNB-291 are sister molecules and the increase in potency is correlating well with the increased production cost of the experimental therapeutic molecule.

The MAC-16 cancer is a model for all CCK-related cancers, which is specific for the cancer biology, the biological target, and not based on the origin – the location- of specific cancer. Based on tumour biology PNB-291 is a targeted therapy for gastric, liver, lung and brain cancer.

Preclinical development studies: DMPK studies with PNB-291 indicated that the NCE was stable in rat, dog, and human liver microsomes. One site of metabolism is protected by a fluorine atom and the benzyl group is best in SAR for affinity and selectivity. Most importantly, with a low polar surface area, a high membrane penetration was achieved. Studies, including CaCo2 permeability and plasma protein binding, demonstrated favourable druggable properties of PNB-291.

PNB-291 is containing a second fluorine atom in the para phenyl position, blocking hydroxylating metabolism and thus, enhancing the oral bioavailability.

Synthetic chemistry: PNB-291 synthetic scheme has only two steps and involves highly economical raw materials. PNB-291 can be synthesized on a large scale with high purity exceeding 99.7%.

Ongoing studies: Preclinical toxicology and safety pharmacology regulatory studies in accordance with ICH guidelines are to be launched.