N-Methyladenosine (m6A) is a methylated adenine residue and an endogenous urinary nucleoside product of the degradation of transfer ribonucleic acid (tRNA). Adenosine methylation is directed by a large m6A methyltransferase complex containing METTL3 as the SAM-binding sub-unit. In vitro, this methyltransferase complex preferentially methylates RNA oligonucleotides containing GGACU and a similar preference was identified in vivo in mapped m6A sites in Rous sarcoma virus genomic RNA and in bovine prolactin mRNA. More recent studies have characterized other key components of the m6A methyltransferase complex in mammals, including METTL14, Wilms tumor 1 associated protein (WTAP) and KIAA1429. Following a 2010 speculation of m6A in mRNA being dynamic and reversible, the discovery of the first m6A demethylase, fat mass and obesity-associated protein (FTO) in 2011 confirmed this hypothesis and revitalized the interests in the study of m6A. A second m6A demethylase alkB homolog 5 (ALKBH5) was later discovered as well. The biological functions of m6A are mediated through a group of RNA binding proteins that specifically recognize the methylated adenosine on RNA. These binding proteins are named m6A readers. The YT521-B homology (YTH) domain family of proteins (YTHDF1, YTHDF2, YTHDF3, and YTHDC1) have been characterized as direct m6A readers and have a conserved m6A-binding pocket. These m6A readers, together with m6A methyltransferases (writers) and demethylases (erasers), establish a complex mechanism of m6A regulation in which writers and erasers determine the distributions of m6A on RNA, whereas readers mediate m6A-dependent functions. m6A has also been shown to mediate a structural switch termed m6A switch. Considering the versatile functions of m6A in various physiological processes, it is thus not surprising to find links between m6A and numerous human diseases; many originated from mutations or single nucleotide polymorphisms (SNPs) of cognate factors of m6A. The linkages between m6A and numerous cancer types have been indicated in reports that include stomach cancer, prostate cancer, breast cancer, pancreatic cancer, kidney cancer, mesothelioma, sarcoma, and leukemia. The depletion of METTL3 is known to cause apoptosis of cancer cells and reduce the invasiveness of cancer cells, while the activation of ALKBH5 by hypoxia was shown to cause cancer stem cell enrichment. m6A has also been indicated in the regulation of energy homeostasis and obesity, as FTO is a key regulatory gene for energy metabolism and obesity. SNPs of FTO have been shown to associate with body mass index in human populations and occurrence of obesity and diabetes. The influence of FTO on pre-adipocyte differentiation has been suggested. The connection between m6A and neuronal disorders has also been studied. For instance, neurodegenerative diseases may be affected by m6A as the cognate dopamine signaling was shown to be dependent on FTO and correct m6A methylation on key signaling transcripts. The mutations in HNRNPA2B1, a potential reader of m6A, have been known to cause neurodegeneration.

Didox is a simple, synthetic antioxidant and a ribonucleotide reductase inhibitor with activity against retroviruses. Didox inhibits retrovirus replication by depleting the deoxynucleotides obligatory for the synthesis of the proviral DNA intermediate of retrovirus replication. It also increases the radiosensitivity of cancer cells by inhibition of ribonucleotide reductase, resulting in a reduction of BCL-2 mediated resistance to apoptosis. Didox has been found to reduce the levels of oxidative injury markers in the brains of HIV patients with dementia. Didox has been evaluated in various phase I and phase II trials but Didox did not demonstrate any efficacy response in patients.

Arotinoid acid (Ro 13-7410, TTNPB) is the third generation of synthetic retinoid, which was developed for the treatment of psoriasis and other hyperkeratotic skin disorders. The therapeutically active dose is less than 0.5 ug/kg body weight/day. Arotinoid Acid is an agonist of RAR with IC50 values of 3.8nM, 4nM and 4.5nM for RARα, RARβ and RARγ, respectively. Naturally occurring vitamin A-like compounds such as all-trans-retinoic acid (atRA) are responsible for regulating growth and differentiation in the cell, and many of them have shown promising anticancer effects. Bioassays in vivo and in culture showed that TTNPB is more potent than atRA, mainly because of its higher molecular stability. The effects of TTNPB, which include control of epidermal keratinocytes and murine teratocarcinoma cells and antiproliferative effects on Kaposi´s sarcoma, breast cancer, cervical carcinoma, and leukemia cells have been known for some time. Furthermore, TTNPB proved to be 100 times more effective than atRA in inhibiting the growth of breast cancer cells. However, TTNPB is more teratogenic than atRA, which limits its use as a chemotherapeutic agent in humans. Arotinoid acid (AGN193198) has being shown to be useful for the treatment of pancreatic cancer among other types of cancer.

Delta-tocotrienol is a member of vitamin E family. Tocotrienols are natural compounds found in a number of vegetable oils, wheat germ, barley, and certain types of nuts and grains. Tocotrienol-rich products such as DeltaGold® are gerally recognized as safe and are commecrially available as a dietary supplements. Tocotrienols possess powerful neuroprotective, antioxidant, anti-cancer and cholesterol lowering properties. The mechanism involved in anti-cancer activity of tocotrienols are still unclear, and include activation of caspases, downregulation of Bcl-2 and cyclin D, inhibition of angiogenesis, inhibition of cell proliferation though cell cycle arrest, downregulation of Raf/Erk pathway.

Cyclopamine is an inhibitor of hedgehog (Hh) signaling, likely via direct inhibition of Smoothened, the accessory protein to the putative Hh receptor Patched. Cyclopamine is a teratogen isolated from the corn lily that causes usually fatal birth defects. It can prevent the fetal brain from dividing into two lobes (holoprosencephaly) and cause the development of a single eye. Cyclopamine can also be used to induce differentiation of human embryonic stem cells (hESCs) into hormone-expressing endocrine cells. In the very first at any time human affected person with metastatic pancreatic most cancers who was administered intravenous cyclopamine on a compassionate, experimental basis in Germany, cyclopamine had to be discontinued because of emergence of neurologic toxicities and hematologic toxicities. That may possibly severely impede or even prevent scientific trials with this promising therapeutic technique.

LG 100268 (LGD 1268) is retionid X receptor agonist, originated in Ligand Pharmaceuticals. LG 100268 demonstrated efficacy in preclinical models of obesity, breast and lung cancer.

Сalpeptin is useful cell-penetrative calpain inhibitor. Calpeptin inhibits the cell growth of ER (estrogen receptor) positive breast cancer cells, such as MCF-7, T-47D, and ZR-75-1 in the presence of Estradiol. Studies in rodent and cell culture models of Parkinson's disease suggest that treatment with calpain inhibitor calpeptin can prevent neuronal death and restore functions. The combination of histone deacetylase inhibitors and calpeptin inhibited the growth of two distinctly different types of breast cancer cells and could have wide clinical applications. Calpeptin is a promising antitumor agent for pancreatic cancer.

C-1311 is an imidazoacridinone analog. It is a next-generation investigational anticancer drug. It is an antitumor inhibitor of topoisomerase II and FMS-like tyrosine kinase 3 receptor. It was evaluated in phase I and II clinical trials for the treatment of various types of tumors. Mild treatment-related adverse events were thrombocytopenia, anemia, nausea, vomiting and diarrhea. Serious adverse event is neutropenia.

Diallyl disulfide (DADS) or allyl disulfide is the main organosulfur ingredient in garlic, with known antioxidant and anti-inflammatory activities. It has been shown to have multi-targeted antitumor activities in a variety of cancer cells Experiments in vitro have revealed, that diallyl disulfide inhibits the metastasis of type Ⅱ esophageal-gastric junction adenocarcinoma cells via NF-κB and PI3K/AKT signaling pathways. At the same time, was shown the drug suppresses cell stemness, proliferation, metastasis and glucose metabolism in breast cancer stem cells partly through the inhibition of CD44/PKM2/AMPK. Besides diallyl disulfide can be a promising agent for the treatment of emphysema, this was discovered in experiments on rats. And also drug shows protective effects against acetaminophen (AAP)-induced acute hepatotoxicity.

Coumestrol is one of the major phytoestrogens, which is abundant in soybeans, legumes, and spinach. It competitively binds the estrogen receptors ERα and ERβ. Besides coumestrol is an endogenous antagonist of the human pregnane X receptor. It is known, that antagonizing the action of the human nuclear xenobiotic receptor pregnane X receptor (PXR) may have important clinical implications in preventing drug-drug interactions and improving therapeutic efficacy. Coumestrol epigenetically suppresses cancer cell proliferation, due to its inhibition of natural haspin kinase. Coumestrol exhibits broad anti-cancer effects against skin melanoma, lung cancer, breast cancer and some others cancer cell growth. Besides, was also shown the beneficial effects of coumestrol in various biological processes including, neuroprotective effects on the nervous system, and the function of the female reproductive system. However, the experiments for male rodents have strongly suggested a deleterious effect of oral, low concentration phytoestrogen content in adult male diets.