Motesanib (AMG 706), a novel nicotinamide, was identified as a potent, orally bioavailable inhibitor of the VEGFR1/Flt1, VEGFR2/kinase domain receptor/Flk-1, VEGFR3/Flt4 and Kit receptors. Motesanib was expected to reduce vascular permeability and blood flow in human tumours. A phase III trial of motesanib in combination with paclitaxel and carboplatin in non-squamous NSCLC has been terminated by Takeda and subsequently the development was discontinued. Motesanib has also been investigated up to phase II in breast, thyroid, colorectal and gastrointestinal stromal tumours. However, development has been discontinued in these indications.

ARN-810 (GDC-0810) is a novel, orally bioavailable, estrogen receptor antagonist that induces proteasomal estrogen receptor degradation in breast cancer cell lines at picomolar concentrations and tumor regression in tamoxifen-sensitive and resistant BC xenograft models. Results from a first-in-human phase I/IIa study of ARN-810 indicate that it is tolerable and may benefit some postmenopausal women with advanced estrogen receptor-positive breast cancer. Development of ARN-810 was discontinued.

Savolitinib (AZD6094, HMPL-504) has been demonstrated to inhibit the growth of tumors in a series of preclinical disease models, selectively for those tumors with aberrant c-Met signaling. Phase I dose escalation studies were initiated in Australia and China in 2012 and 2013 respectively. Savolitinib has demonstrated good safety and tolerability and favorable pharmacokinetic properties in late stage cancer patients, and has shown encouraging anti-tumor activity in several tumor-types, in particular for metastatic Papillary Renal Cell Cancer (PRCC). Phase II, study designed to evaluate the efficacy and safety of savolitinib in patients with locally advanced or metastatic PRCC. Approximately 20 centers in the United States, Canada, and Europe will participate in the study. The primary objective of this study is to assess the anti-tumor activity in patients with PRCC as measured by overall response rate according to Response Evaluation Criteria in Solid Tumours (“RECIST”). The secondary objectives for this study are to: assess the progression free survival and duration of response in patients with PRCC according to RECIST; assess the safety and tolerability in the treatment of patients with PRCC; characterize the pharmacokinetics and pharmacodynamics of savolitinib and metabolites following administration to steady state after multiple dosing when given orally.

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.

Bevirimat (3-O-(3',3'-dimethylsuccinyl) betulinic acid or MPC-4326 or PA-457) potently inhibits replication of both WT and drug-resistant HIV-1 isolates and demonstrate that the compound acts by disrupting a late step in Gag processing involving conversion of the capsid precursor (p25) to mature capsid protein (p24). Bevirimat inhibits replication of both wild-type and drug-resistant HIV-1 isolates in vitro, achieving similar 50% inhibitory concentration values with both categories. Serial drug passage studies have identified six single amino acid substitutions that independently confer bevirimat resistance. These resistance mutations occur at or near the CA-SP1 cleavage site, which is not a known target for resistance to other antiretroviral drugs. Bevirimat has been in phase 2 trial for the treatment of HIV infections. Bevirimat has demonstrated a consistent pharmacokinetic profile in healthy volunteers and HIV-infected patients. The demonstration of an antiviral effect following a single oral dose of bevirimat validates maturation inhibition as a potential target for antiretroviral therapeutics in humans.

Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. Basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy. Basimglurant is being under development by Roche for the treatment of treatment-resistant depression (as an adjunct). It is in phase II clinical trials for this indication.

Andrographolide, a diterpenoid, is known for its anti-inflammatory effects. It can be isolated from various plants of the genus Andrographis, commonly known as 'creat'. Andrographolide has been tested for its anti-inflammatory effects in various stressful conditions, such as ischemia, pyrogenesis, arthritis, hepatic or neural toxicity, carcinoma, and oxidative stress. Apart from its anti-inflammatory effects, andrographolide also exhibits immunomodulatory effects by effectively enhancing cytotoxic T cells, natural killer (NK) cells, phagocytosis, and antibody-dependent cell-mediated cytotoxicity (ADCC). The properties of andrographolide, such as its ability to induce apoptosis of cancer cells and inhibition of DTH, its anti-oxidative and cytoprotective effect, and its ability to enhance CTLs and NK cell activation makes it a potent antiviral agent. Andrographolide inhibited the growth of human breast, prostate, and hepatoma tumors. Andrographolide could be a potent anticancer agent when used in combination with other chemotherapeutic agents.

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.

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.

R-etodolac (SDX-101) is the non-cyclooxygenase 2-inhibiting R-enantiomer of the non-steroid anti-inflammatory drug etodolac (1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid). The absolute configuration of the enantiomer is R-(-)-etodolac. R-etodolac specifically bound retinoid X receptor (RXRalpha), inhibited RXRalpha transcriptional activity, and induced its degradation by a ubiquitin and proteasome-dependent pathway. In addition R-etodolac can disrupt the beta-catenin signaling pathway. R-etodolac exerts antineoplastic properties. R-etodolac was in phase 2 studies for the treatment of hematologic malignancies however development was discontinued.