Traditionally, diseases are treated with small molecules that target specific cell types and particles. In diseases such as cancer, the treatment is intended to kill cancer cells, leading to the removal or at least the inhibition of cancer cell proliferation. In other circumstances, a variety of therapeutic molecules have been utilized that lead the disease cells to perform a specific function that they normally do not. Some of our compounds under evaluation and testing have strong anticancer combined with anti-inflammatory activities, a rare combination. It means that these compounds have effective properties against various types of cancers. A second group of antiaging compounds will be taken through pharmacokinetic studies and pre-clinical efficacy trials to determine development priorities.

To date, we has synthesized and evaluated many derivatives for cytotoxic and antiaging activities. This research led to the discovery of the following compounds.

BA368 was identified under a research and development agreement with the Palacky University. Various tests on our compounds for different indications have yielded encouraging initial test results on proliferative diseases like psoriases. BA368 is a cytokinin which was later discovered as naturally occurring. Cytokinins are important phytohormones that play a key role in the regulation of plant growth and development. While some cytokinin bases have cytoprotective effects and are able to induce differentiation of some leukemia cell lines and keratinocytes, several natural cytokinin ribosides (CKRs) have antiproliferative effects against a range of human cell lines. Their antiproliferative activity has been demonstrated in vivo using several animal and xenograft models. Most of the data related to the mechanism of action of cytokinin ribosides (CKRs) came from the studies of natural compounds iPR, kinetin riboside (KR) and BAPR (“classical” CKRs). Depending on the cell line, CKRs induced apoptosis, G1 and/or G2/M block in treated cells. Other observed cell cycle effects include suppression of cyclin D1 and D2 transcription, genotoxic stress, JNK activation, inhibition of farnesyl-protein transferase activity, suppression of NF-κB and Akt signaling and changes in the levels of pro- and antiapoptotic proteins. According to a microarray study, iPR induces expression of genes involved in the stress-induced cell cycle arrest like PPP1R15A, DNAJB9, DDIT3, and HBP1. A newly developed cytokinin riboside is also 6-(2-hydro-3-methoxybenzylamino)purine riboside (2OH₃MeOBAPR). We recently showed that 2OH₃MeOBAR is the most active cytokinin riboside we have studied so far (median NCI60 GI₅₀ = 0.19, the 1^st quartile = 0.10, the 3^rd quartile 0.43, min 0.02, max 15.7 µM). It differs from the other cytokinins by inhibition of cell proliferation and induction of the cell death without causing a pronounced ATP depletion. The compound has also strong growth inhibitory activity of human keratinocytes. In May 2013, BioApex and Palacký University in Olomouc licensed BA368 to Psortech Dermal Sciences LLC, an early stage specialty skincare company based in Santa Fe, NM, USA and focused on improving skin through science.

BA1248, also developed in-house, is an unusual betulinic acid derivative with potent in vitro anticancer activity against human cancer cell lines as well as high solubility in aqueous media like blood serum. To date, we have synthesized small molecule compounds of BA248. The compound has shown to be active in melanoma cell cultures and to induce cell death (apoptosis).

BA1248 is derived from betulinic acid known as a naturally occurring pentacyclic triterpenoid which has anti-retroviral, anti-malarial, and anti-inflammatory properties; more recently, it was discovered to have potential as an anticancer agent, inhibiting topoisomerase. In 1995, betulinic acid was reported as a selective inhibitor of human melanoma. Since then, further research has demonstrated that betulinic acid induces apoptosis in human melanoma in vitro and in vivo model systems. Currently, a development program is underway with the assistance from the Rapid Access to Intervention Development program of the National Cancer Institute, USA.

After a preclinical evaluation in xenograft models, we determined that BA1248 is not effective enough to warrent preclinical and clinical development. We have, therefor, terminated further work on this compound.

BA2123 is an oral nucleoside analogue prodrug that acts through a dual mechanism. The compound interferes with DNA synthesis by causing single-strand DNA breaks and induces arrest of the cell division cycle at G2 phase.

Both BA2123 and its major metabolite, have demonstrated potent anti-tumour activity in both blood and solid tumours in preclinical studies. In a metastatic mouse model, it was shown to be superior to gemcitabine (Gemzar®; Lilly) or 5-FU, two widely used nucleoside analogues, in delaying the onset and growth of liver and other metastasis. BA2123 exhibits strong antiangiogenic properties on viability, proliferation, cell cycling and migration, or tube formation of primary endothelial cells (HUVEC, HMEC-1).

We have initiated three preclinical trials to evaluate safety and pharmacokinetics of a variety of dosing schedules for BA2123 in both solid and haematological tumours, laying the foundation for future Phase 1 and combination studies with other anti-cancer agents.

At the very center of our cellular protective pathway is a protein called “Nrf2” that serves as a “master regulator” of the body’s antioxidant response. A major mechanism in the cellular defense against oxidative or electrophilic stress is activation of the Nrf2-antioxidant response element signaling pathway, which controls the expression of genes whose protein products are involved in the detoxication and elimination of reactive oxidants and electrophilic agents through conjugative reactions and by enhancing cellular antioxidant capacity. Recent papers show that Nrf2 also regulates genes involved in the production of a wide range of antioxidant enzymes (including SOD, glutathione, and catalase), and detoxification or ‘‘stress-response’’ genes. When activated, Nrf2 turns on the production of specific antioxidants the body needs to fight cellular stress effectively. Certain phytochemicals (BA1521 is a natural cytokinin derivative) synergistically activate Nrf2. Turning on Nrf2 creates a cascading effect that results in the production of several very powerful antioxidants. These antioxidants do a much better job at combating cellular stress than dietary, vitamin or phytochemical source individually. Several antioxidant enzymes, including superoxide dismutase (SOD), glutathione, and catalase are activated through the Nrf2 pathway. Many scientists believe that Nrf2 activation is the “future” of cellular protection and health promotion. BA1521 has been one of the most effective products at supporting health we have ever formulated. It was tested successfully preclinically for toxicity and in a Pilot Clinical Research Study to evaluate BA1521™ RCTS (30 subjects) clinical effectiveness and subject tolerance for the treatment of signs and symptoms of psoriasis vulgaris. The Study was a single center, double blinded, repeated dose study, conducted at the Dermatology Department of the Military Hospital in Olomouc, Czech Republic.