PNB-101 for the Treatment of Lung and Stomach Cancers
|Therapeutic target||Cholecystokinin Receptors|
|Therapeutic indication||Gastric cancer|
|Secondary indications||Lung cancer (only small cell lung cancer)|
Background about target
Lung cancer is the most (33.8/100.000) and fourth most (13.5/100.000) popular cancer in male and female, respectively. Lung cancer is also the most popular cause of cancerous mortality, which accounted for 1.38 million deaths worldwide (18.2% in total) in 2008. The standard chemotherapy for late-stage non-small cell lung cancer is platinum-based (cisplatin, carboplatin, oxaliplatin) dual therapy (Pfister et al., 2004; Socinski et al., 2007). Based on a literature review, the CCK2 receptor is a validated molecular target for lung cancer. Moody published recently (Moody et al 2015; http://jpet.aspetjournals.org/content/299/3/1154.long) and the CCK2 antagonist CI-988 was an ideal candidate for the treatment of lung cancer. This is a final re-confirmation of his earlier work and also supports the link inflammation and cancer.
The signaling pathway of CCK via the CCK 2/ gastrin receptors in cancer underpins the bioactivity found in vitro and in vivo. After stimulating CCK or gastrin, CCK-B/gastrin or CCK-C receptors will undergo a conformational change, which results in the isolation of Gα with two other Gβγ subunits of G-protein to interact with CCK receptor. Gα will then be activated and stimulates its downstream second messengers, which elicit various cellular processes relating to proliferation and survival of the cell. Initial results are in line with the literature. Using a C38 murine lung cell line, in vitro anti-cancer activity, was obtained better than CI-988. In a xenograft study with the human transplanted lung cancer cell line NCI H727 more than 80% inhibition of tumour growth was obtained in nude mice after 28 days in responders by oral administration. SAR optimisation was completed and inflammation was extended from the usual inflammation to neuro-inflammation for PNB-102 and from inflammation to cancer for PNB-101.
Preclinical development studies: PNB-102 is the chlorinated sister molecule of PNB-101 and its higher lipophilicity is key in CNS applications, such as Parkinson’s disease. The bioavailability of PNB-101 is enhanced by 700% compared to PNB-001 and the interaction of the molecule with dopamine was well investigated in vitro and in vivo.
Synthetic chemistry: PNB-101 synthetic scheme has only two steps and involve highly economical raw materials. PNB-102 is synthesized from chlorobenzene, which interestingly, is even cheaper than benzene and combined with mucochloric acid, which is available from furfural, it will be one of the cheapest API on the market. PNB-102 was successfully synthesized in good yields and high purity.
Ongoing studies: Preclinical toxicology and safety pharmacology regulatory studies in accordance to ICH guidelines will be initiated after PNB-081.