Chugai Pharma Europe is developing CH-5132799, a phosphatidylinositol-3-kinase (PI3K) inhibitor, for the treatment of solid tumours. CH-5132799 is a selective class I PI3K inhibitor with potent antitumor activity against tumors harboring the PIK3CA mutations. CH-5132799 selectively inhibits class I PI3Ks, PI3Kα (IC50 = 0.014 uM ), PI3Kβ (IC50 = 0.12 uM ), PI3Kδ (IC50 = 0.50 uM ), PI3Kγ (IC50 = 0.036 uM ), but shows less inhibition of class II PI3Ks, class III PI3k and mTOR and also no inhibitory activity (IC50 > 10 uM) against 26 protein kinases. CH-5132799 exhibits more inhibitory activities against PI3Kα with oncogenic mutations E542K (IC50 = 6.7 nM), E545K (IC50 = 6.7 nM) and H1047R (IC50 = 5.6 nM) than wild-type PI3Kα. CH-5132799 treated breast cnacer KPL-4 cells, which harbor the PIK3CA mutation, phosphorylation of Akt and its direct substrates, PRAS40 and FoxO1/3a and phosphorylation of downstream factors, including S6K, S6 and 4E-BP1, are effectively suppressed. Cancer cell lines harboring PIK3CA mutations are significantly sensitive to CH-5132799. CH-5132799 is orally available and showed significant antitumor activity in PI3K pathway-activated human cancer xenograft models in mice. CH-5132799 is in phase I study to evaluate safety, pharmacokinetics and activity of CH-5132799 administered orally as a single agent in patients with advanced solid tumors.

Withaferin A is one of the most bioactive phytoconstituents of Withania somnifera, a well-known herb in Ayurvedic medical tradition of India. Due to the lactonal steroid's potential to modulate multiple oncogenic pathways, Withaferin A has gained much attention as a possible anti-neoplastic agent. Systematic research on the evaluation of anticancer activities of withaferin A was started around the 1970s. Since then, a large number of studies have demonstrated the ability of withaferin A to suppress the in vivo growth of various human cancer cells’ xenograft tumors as well as experimentally induced carcinogenesis in different rodent models. It has being reported that withaferin-A reduced the growth of human prostate cancer (PC3) cells tumor xenograft in nude mice by blocking the tumor angiogenesis and inducing intratumoral apoptosis. According to this study, i.p. administration of withaferin-A caused regression of implanted tumor cells by decreasing the expression of angiogenesis marker CD31, inducing the expression of proapoptotic protein Bax, and activating caspase-3 via inhibition of nuclear factor-κB (NF-κB) signaling pathway. In a separate study, intratumoral administration of withaferin-A arrested PC3 cells’ xenograft tumor growth in mice by inducing tumor cell death via upregulation of prostate apoptosis response-4 (Par-4). Anticancer activity of withaferin-A has also being demonstrated for gynecological cancer, melanoma, thyroid, gastrointestinal and other types of cancer. Mechanistic basis of the anticancer effects of withaferin-A includes: (1) reinforcement of cellular antioxidant and/or detoxification system; (2) suppression of inflammatory pathways; (3) selective inhibition of tumor cell proliferation and induction of apoptosis; (4) suppression of tumor angiogenesis; (5) blockade of epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastasis; (6) alteration of tumor cell metabolism; (7) immunomodulation; and (8) eradication of cancer stem cells.

24-Hydroxycalcidiol (24,25-dihydroxy vitamin D3) is a circulating metabolite of vitamin D3. 24,25(OH)2D3 functions by activation of Vitamin D receprtor and promotion of ostecalcin expression, but is less effective than other D3 metabolite, 1alpha,25(OH)2D3. There is conflicting evidence on efffect of 24-hydroxycalcidiol on bone metabolism. In several animal studies it was demonstrated that 24-hydroxycalcidiol was able to stimulate calcification of bone and restore the reduction in bone mineral apposition rate. However, no beneficial effect of 24R,25(OH)2D3 treatment of postmenapausal women on bone mineral density or bone loss and calcium metabolism were observed.

Calanolide A is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) originally extracted from a tropical tree (Calophyllum lanigerum) in the Malaysian rain forest. Viral life-cycle studies indicate that calanolide A acts early in the infection process, similar to the known HIV reverse transcriptase (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition assays, calanolide A potently and selectively inhibits recombinant HIV type 1 RT but not cellular DNA polymerases or HIV type 2 RT within the concentration range tested. Phase I studies have found that calanolide A is well tolerated. Consequently, it has potential clinical applications in combination with other antiviral drugs to suppress HIV-1 mutants. Nevertheless, the development of calanolide A has been delayed due to its low therapeutic index (range: 16–279), non-ideal antiviral activity, and the complexity of its extraction from plants

Salvinorin A has been reported to be the most potent naturally occurring hallucinogen, with an effective dose in humans in the 200- to the 1,000-μg range when smoked; it has been reported to induce an intense hallucinatory experience in humans, with a typical duration of action being several minutes to an hour or so. Salvinorin A is a highly selective agonist of the kappa-opioid receptor (KOR) with few off-target effects. It is a potent and selective dilator of the cerebral vasculature, exhibits rapid penetration through the blood-brain barrier, has potent anti-inflammatory properties, and has the ability to preserve neurovascular unit integrity. As such, salvinorin A is an ideal compound for the prevention and treatment of cerebral vasospasm following subarachnoid hemorrhage.

Licochalcone A (LicA) is a flavonoid isolated from the famous Chinese medicinal herb Glycyrrhiza uralensis Fisch and has a wide spectrum of pharmacological activities such as anti-oxidant, anti-bacterial, anti-viral, and anti-cancer. However, its pharmacological mechanism is not well defined. The anti-Inflammatory effects of LicA on IL-1β-Stimulated human osteoarthritis chondrocytes was reached by activating Nrf2 signaling pathway. LicA showed anti-proliferative and apoptotic effects in breast cancer cells through regulating Sp1 and apoptosis-related proteins in a dose- and a time-dependent manner. In addition, the chemotherapeutic potential of LicA for treatment of human cervical cancer was achieved by inhibition of PI3K/Akt/mTOR signaling.

MK-8776 (SCH900776) is inhibitor of CHK1. It was tested in clinical trials against acute myeloid leukaemia, solid tumors and lymphoma.