Amcasertib is an orally administered investigational agent designed to inhibit cancer stemness pathways, including Nanog, by targeting stemness kinases. Amcasertib is undergoing multiple Phase I and Phase II studies as monotherapy and combination therapy for treating a range of tumor types.

p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. Based on X-ray cocrystal structures a model of AMG 232 bound to MDM2 was developed. The model shows that the m-chlorophenyl, the p-chlorophenyl, and C-linked isopropyl fragments of AMG 232 bind to the Leu 26(p53), Trp 23(p53), and Phe 19(p53) pockets of MDM2, respectively. The carboxylic acid forms a salt bridge with His 96 and the isopropyl sulfone forms a novel interaction with the glycine shelf region of MDM2. AMG 232 in phase II in combination with trametinib and dabrafenib in subjects with metastatic melanoma; in phase I for the treatment of solid tumors, multiple myeloma and Acute Myeloid Leukemia.

Vilaprisan, a small molecule progesterone receptor antagonist is being developed by Bayer HealthCare Pharmaceuticals (formerly Bayer Schering Pharma) for the treatment of endometriosis and uterine leiomyoma. Hormonal imbalance observed in women with endometriosis is a potential target for treating endometriosis. Vilaprisan is a highly selective steroidal progesterone receptor modulator (SPRM). It is a partial agonist of progesterone receptor, which means that the drug activates progesterone receptors to a certain degree upon binding. This triggers a cascade of biochemical reactions that result in the suppression of prostaglandin production. This, in turn, relieves symptoms such as pain and bleeding. Modulating progesterone by taking vilaprisan might help in treating endometriosis over the long term. Phase I and II studies give encouraging results on the efficacy of vilaprisan at different doses. Like other SPRMs, vilaprisan induces benign changes of endometrium (PR modulator-associated endometrial changes, PAECs). These disappear as treatment is discontinued. Unlike GnRHa treatment, neither UPA nor vilaprisan induce hypoestrogenism and associated symptoms. Phase III studies are ongoing to confirm efficacy and safety of vilaprisan in long-term treatment of symptomatic fibroids.

Uprosertib is an oral potent Akt inhibitor which acts equally on Akt1, Akt2 and Akt3. The drug is under clinical development in combination with trametinib for the treatment of different cancers, including melanoma, myeloma, breast, endometrial, cervical cancer, etc.

Novartis Oncology (previously Novartis) is developing nazartinib (formerly EGF 816), a third generation mutant-selective tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), for the treatment of solid malignancies, with a focus on non-small cell lung cancer. Nazartinib is a covalent mutant-selective EGFR inhibitor, with Ki and Kinact of 31 nM and 0.222 min−1 on EGFR(L858R/790M) mutant, respectively. Upon oral administration, nazartinib covalently binds to and inhibits the activity of mutant forms of EGFR, including the T790M EGFR mutant, thereby preventing EGFR-mediated signaling. This may both induce cell death and inhibit tumor growth in EGFR-overexpressing tumor cells. EGFR, a receptor tyrosine kinase mutated in many tumor cell types, plays a key role in tumor cell proliferation and tumor vascularization. EGF816 preferentially inhibits mutated forms of EGFR including T790M, a secondarily acquired resistance mutation, and may have therapeutic benefits in tumors with T790M-mediated resistance when compared to other EGFR tyrosine kinase inhibitors. As this agent is selective towards mutant forms of EGFR, its toxicity profile may be reduced as compared to non-selective EGFR inhibitors which also inhibit wild-type EGFR.

Kirax Corporation (formerly Tigris Pharmaceuticals) was developing AFP-464, a lysyl prodrug of aminoflavone for the treatment of solid tumours. AFP-464 is an antitumor agent which was in phase II clinical trials, acts against estrogen-positive breast cancer (ER+). AFP-464, has a unique mechanism of action by activating aryl hydrocarbon receptor (AhR) signaling pathway. Preclinical studies into AFP-464's mechanism of action have shown that AFP-464 is converted to metabolites, which bind covalently to DNA, resulting in p53 activation and apoptosis. AFP-464 has shown a unique pattern of growth inhibitory activity in the NCI's 60 tumor cell line screen, with breast, ovarian, lung and renal tumor cell lines exhibiting particular sensitivity to the compound. In vivo anti-tumor activity of AFP-464 has been demonstrated in several xenograft studies in mice bearing renal and breast cancer. Preclinical studies have shown that tumors (breast, ovarian, pancreatic and renal) with AhR localized in the cytoplasm are very sensitive to AFP-464 while those with AhR localized in the nucleus are more resistant. AFP-464 was being studied by Tigris Pharmaceuticals in a randomized Phase 2 clinical trial with ER-positive breast cancer patients. However, AFP-464 development was discontinued.

BVD-523 potently and selectively inhibits ERK1 and ERK2 kinases in a reversible, ATP-competitive fashion. Consistent with its mechanism of action, BVD-523 inhibits signal transduction, cell proliferation, and cell survival, most potently in cell lines bearing mutations that activate MAPK pathway signaling. Similarly, single-agent BVD-523 inhibits tumor growth in vivo in BRAF-mutant melanoma and colorectal xenografts as well as in KRAS-mutant colorectal and pancreatic models. BioMed Valley Discoveries is developing ulixertinib, a potent and selective small molecule inhibitor of ERK 1 and 2 kinases, as an oral treatment for cancers harbouring mutations in the MAPK signaling pathway. Phase I/II development of the drug for advanced cancers including, acute myeloid leukaemia and myelodysplastic syndromes is underway in the US. A phase I trial is underway in the US for pancreatic cancer.

9cUAB30 is a synthetic analog of 9-cis-RA with little or no RAR-binding activity relative to 9-cis-RA and other RA. 9cUAB30, is a selective rexinoid for the retinoid X nuclear receptors (RXR). Retinoid 9cUAB30 binds to and activates retinoid X receptor (RXR) homodimers and/or and retinoic acid receptor (RAR)/RXR heterodimers, which may result in the dissociation of corepressor protein and the recruitment of coactivator protein, followed by transcription of downstream target genes into mRNAs and protein translation. Gene transcription regulated by these transcription factors may result in inhibition of cell proliferation, induction of cell differentiation, and apoptosis of both normal cells and tumor cells. 9cUAB30 displays substantial chemopreventive capacity with little toxicity and is being translated to the clinic as a novel cancer prevention agent. 9cUAB30 has been assessed in vitro with human cell cultures. Human hepatocytes demonstrated no signs of cytotoxicity with treatment of 9cUAB30 up to 50 umol/L, although when human breast cancer cells were treated with 9cUAB30, they showed a significant inhibition of cell proliferation and apoptotic levels 2.5to 3.5 times the levels of untreated cells. 9cUAB30 inhibits telomerase and induces apoptosis in HL60 cells.

Lobucavir is a new anti-cytomegalovirus infection agent, manufactered by Bristol Myers Squibb, Inc. Lobucavir is a cyclobutyl analog of guanine with broad spectrum antiviral activity against most herpes viruses and Hepatitis B. Lobucavir was shown to inhibit herpes simplex virus (HSV) DNA polymerase after phosphorylation by the HSV thymidine kinase. The drug was well tolerated with few side effects. Lobucavir had been in phase III clinical trial for the treatment of Hepatitis B, Herpes simplex virus infections and in phase II for the treatment of Cytomegalovirus infections. All these studies were discontinued.