AT7519M or AT7519, a small molecule inhibitor of cyclin-dependent kinases 1, 2, 4, 5, and 9, participated in phase II clinical trials in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). As a result, in CLL, some patients had tumor reductions, but the objective response rate (ORR) was low. In MCL, activity was noted with ORR of 27%. In addition, AT7519M was studied in patients with previously treated multiple myeloma, to understand whether the drug alone or in combination with bortezomib were effective treatments. Recent experiments also have shown that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. It is known, that MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment.

SNX-5422 (also known as PF-04929113) is a synthetic, novel, small molecule Hsp90 inhibitor with potential antineoplastic activity. Hsp90 is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signaling proteins, such as HER2/ERBB2, AKT, RAF1, BCR-ABL, and mutated p53, as well as many other molecules that are important in cell cycle regulation or immune responses. Inhibition of Hsp90 by SNX-2112 may result in the proteasome degradation of oncogenic client proteins, including HER2/ERBB2, and the inhibition of tumor cell proliferation. SNX-5422 is originally developed by Pfizer and Serenex, Inc., and the phase I clinical trials for it has been completed in the treatment of solid tumors. Although the mechanism of action remains to be fully elucidated, SNX-5422, which is a prodrug, is rapidly converted to SNX-2112 that accumulates in tumors relative to normal tissues.

Voxtalisib (SAR245409, XL765) is an orally available inhibitor of PI3K and the mammalian target of rapamycin (mTOR), which are frequently activated in human tumors and play central roles in tumor cell proliferation. Exelixis discovered Voxtalisib internally and out-licensed the compound to Sanofi. Voxtalisib is being evaluated by Sanofi as a single agent and in multiple combination regimens in a variety of cancer indications. Clinical trials have included a single agent phase 2 trial in Non-Hodgkin’s lymphoma, combination phase 1b/2 trials with temozolomide in patients with glioblastoma, with letrozole in hormone receptor positive breast cancer, with bendamustine and/or rituximab in lymphoma or leukemia, and a phase 1 trial in combination with a MEK inhibitor. Voxtalisib is a highly selective, potent and reversible ATP-competitive inhibitor of pan-Class I PI3K (α, β, γ, and δ) and mTORC1/mTORC2. It is orally active, highly selective over 130 other protein kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 phosphorylation in multiple tumor cell lines with different genetic alterations affecting the PI3K pathway.

GlaxoSmithKline is developing Camicinal (GSK 962040), an oral motilin receptor agonist for the treatment of gastroparesis. Camicinal is being evaluated in phase II for diabetic gastroparesis and gastroparesis. Camicinal is well tolerated in multiple trials with no serious drug-related adverse events or changes in ECG chemistry when given as a single oral dose of up to 125 mg. Although larger studies are soon to be reported, current evidence shows that adverse events occurred evenly between the placebo and treatment groups, and was generally mild. Camicinal has been previously shown to increase gastric emptying in volunteers after repeat dosing over 14 days with no tolerance effect in patients with gastroparesis and type 1 diabetes. Camicinal meets the criteria of an ideal motilin agonist. The compound activates long-lasting cholinergic contractility at low doses in the antrum with greater efficacy than current therapeutic options.

Quisinostat is an orally bioavailable potent histone deacetylase inhibitor, specifically selected due to its sustained inhibition of HDAC1 in solid tumor tissues and prolonged period of half-elimination from tissues. Phase 2 clinical trials are ongoing in patients with platinum-resistant ovarian cancer and non-small cell lung cancer (NSCLC). Quisinostat is active in the treatment of patients with relapsed or refractory Sézary syndrome. The most common drug-related adverse events reported in this trial were: nausea, diarrhea, asthenia. Grade 3 adverse events were also reported: hypertension, lethargy and pruritus.

XL-888 is a highly potent and orally bioavailable ATP-competitive inhibitor of HSP90, a molecular chaperone protein that regulates the activity and stability of a range of key regulatory proteins, including a number of kinases implicated in cancer cell growth and survival. In preclinical studies, XL-888 has been shown to inhibit the proliferation of a broad panel of human tumor cell lines, and to induce marked degradation of HSP90 client proteins, including BRAF, MET, and HER2. XL-888 was discovered by Exelixis and is wholly owned by the company. XL-888 is currently in Phase I clinical trials for the treatment of malignant melanoma.

Golvatinib is a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron. Eisai was developing an oral formulation of golvatinib, which acts as both a c-Met inhibitor and a vascular endothelial growth factor receptor 2 antagonist with potential antineoplastic activity. Golvatinib binds to and inhibits the activities of both c-Met and VEGFR-2, which may inhibit tumor cell growth and survival of tumor cells that overexpress these receptor tyrosine kinases. c-Met and VEGFR-2 are upregulated in a variety of various tumor cell types and play important roles in tumor cell growth, migration and angiogenesis. Clinical trials involving several forms of cancer are currently underway.

PF-04691502 is a PI3K/mTOR dual inhibitor. It was tested in phase 2 clinical trials against endometrial cancer and breast cancer, but its development was discontinued due to unacceptable toxicity.

Sapanisertib is an oral dual inhibitor of mTORC1/mTORC2, discovered by Intellikine for the treatment of cancer. The drug is being tested in phase II of clinical trials for different cancers among which are sarcoma, hepatocellular carcinoma, etc. The drug is currently developed by Takeda with breast cancer, renal cancer and endometrial cancer being the main target indications.

Chlorogenic acid is the ester of caffeic acid and (-)-quinic acid. Chlorogenic acid is a naturally occurring plant metabolite and can be found with the related compounds cryptochlorgenic acid and neochlorogenic acid in the leaves of Hibiscus sabdariffa, coffee, potato, eggplant, peaches, and prunes. Chlorogenic acid has been investigated as a dietary supplement to improve glucose intolerant hypoglycemia and non-alcoholic fatty liver disease. It has also been identified as a potential anticancer agent by reducing the expression of HIF-1a and Sphingosine Kinase-1. Chlorogenic acid was also identified as a neuraminidase blocker effective against influenza A virus (H1N1 and H3N2).