BMS-754807 is a small-molecule insulin-like growth factor 1 receptor (IGF-1R) antagonist that was being developed by Bristol-Myers Squibb. BMS-754807 is a potent and reversible inhibitor of the insulin-like growth factor 1 receptor/insulin receptor family kinases (Ki, <2 nmol/L). It is currently in phase II development for the treatment of a variety of human cancers. BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epithelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines (IC50, 5-365 nmol/L); the compound caused apoptosis in a human rhabdomyosarcoma cell line, Rh41, as shown by an accumulation of the sub-G1 fraction, as well as by an increase in poly ADP ribose polymerase and Caspase 3 cleavage. BMS-754807 is active in vivo in multiple (epithelial, mesenchymal, and hematopoietic) xenograft tumor models with tumor growth inhibition ranging from 53% to 115% and at a minimum effective dose of as low as 6.25 mg/kg dosed orally daily. Combination studies with BMS-754807 have been done on multiple human tumor cell types and showed in vitro synergies (combination index, <1.0) when combined with cytotoxic, hormonal, and targeted agents. The combination of cetuximab and BMS-754807 in vivo, at multiple dose levels, resulted in improved clinical outcome over single agent treatment. These data show that BMS-754807 is an efficacious, orally active growth factor 1 receptor/insulin receptor family-targeted kinase inhibitor that may act in combination with a wide array of established anticancer agents.

Indibulin is a novel synthetic compound that was identified in a cell-based screening assay to discover cytotoxic drugs. Indibulin destabilizes microtubules and blocks cell cycle transition specifically at the G2-M phase. Indibulin effectively induces apoptosis through Bcl-2 phosphorylation and Bax translocation in human malignant glioma cells in a p53-independent manner. This agent has been shown to be active against multidrug-resistant (MDR) and taxane-resistant tumour cell lines. Indibulin was used in phase I/II clinical trials of patients with advanced solid tumours (metastatic breast cancer). Pharmacokinetic analysis showed a better tolerability underfeeding condition. Dose-limiting toxicities were nausea and vomiting, which seemed to be related to solvent lactic acid.

Ispinesib (SB-715992) is a potent, specific and reversible inhibitor of kinesin spindle protein (KSP). KSP, also known as HsEg5, is a kinesin that plays an essential role in the formation of a bipolar mitotic spindle and is required for cell cycle progression through mitosis. Ispinesib is the highly specific small-molecule inhibitor of KSP tested for the treatment of human disease. It causes mitotic arrest and growth inhibition in several human tumor cell lines and is currently being tested in multiple phase II clinical trials for treatment of the breast cancer and renal cell cancer.

Varlitinib (Alternative Names: ARRY-334543; ARRY-543; ASLAN-001; Varlitinib tosylate) is a small molecule based reversible pan-HER inhibitor of EGFR, HER2 and HER4. In response to the binding of various ligands, these kinases undergo heterodimerisation and homodimerization, resulting in activation of numerous growth factor signaling pathways, by inhibiting the activation of the HER receptors via drug, effects such as shrinkage of the tumor and longer survival can be anticipated. In a large variety of cancers, the overexpression and/or constitutive activation of EGFR and HER2 are often observed and frequently correlate with poor clinical prognosis. Licensed from Array BioPharma with global rights for all indications, varlitinib is being developed as first-in-class drug for cholangiocarcinoma, gastric and colorectal cancer, and as best-in-class drug for breast cancer.

Acolbifene, the active metabolite of EM-800, was identified as a pure antagonist that acts on both activation domains of the ERs. It is in Phase III clinical trials for the prevention of breast cancer and vasomotor symptoms (Hot flush) in postmenopausal women. Most commonly reported adverse events included irregular menses, leg/muscle cramps, diarrhea, and hot flashes. No serious adverse events were reported.

Pravadoline is the anti-nociceptive agent, which has analgesic efficacy against postoperative pain in humans. Pravadoline inhibits the enzyme cyclooxygenase, but in contrast to cyclooxygenase-inhibiting NSAIDs does not produce gastrointestinal irritation. Pravadoline inhibited the synthesis of prostaglandins in mouse brain both in vitro and ex vivo. Pravadoline demonstrated only weak anti-inflammatory activity relative to its anti-nociceptive potency. Single doses of pravadoline were safe and effective in humans, without serious adverse events. Single oral administration of pravadoline maleate induced acute tubular necrosis in male and female beagle dogs.

Tanaproget (WAY-166989) is a nonsteroidal progesterone receptor agonist. It has been in Phase-II clinical trials as an oral contraceptive. The compound demonstrated a positive preclinical pharmacological profile in the treatment of endometriosis. The level of progesterone receptors in breast tumours can be used to guide the selection of endocrine therapies for breast cancer patients. Radiolabeled analogues of tanaproget have diagnostic potential as PET imaging agents for breast cancer.

Iniparib (BSI-201 or 4-iodo-3-nitrosobenzamide) inactivated poly(ADP-ribose) polymerase by zinc ejection from the first zinc finger of this nuclear protein. Iniparib, either alone or in combination with chemotherapy, had significant antitumor activity in preclinical studies in vitro and in vivo. In June 2013, Sanofi dropped the drug after it failed in a phase III trial of patients with squamous non–small-cell lung cancer and a phase II trial in platinum-resistant ovarian cancer.

Hydroxytamoxifen (Afimoxifene) is an active metabolite of tamoxifen exerting estrogen receptor modulatory function. In addition, hydroxytamoxifen binds to regulates transcriptional activity of the estrogen-related receptor gamma. ASCEND Therapeutics, Inc. was developing TamoGel (4-hydroxytamoxifen gel) for a variety of estrogen-dependent conditions, including breast cancer, cyclic breast pain and gynecomastia.

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor, an enzyme involved in bone resorption. Merck & Co was developing odanacatib, a once-weekly, oral Odanacatib, for the treatment of postmenopausal osteoporosis and osteoporosis in men. Merck & Co. has discontinued development of its cathepsin K inhibitor odanacatib, citing an increased risk of cardiovascular events for the osteoporosis drug.