ABT-751 is an orally bioavailable antimitotic sulfonamide, which binds to the colchicine-binding site on beta-tubulin and inhibits the polymerization of microtubules, leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 had been in phase Ⅱ clinical studies for the treatment of breast cancer; colorectal cancer; non-small cell lung cancer; renal cancer, prostate cancer, but these researches have been discontinued.

Serabelisib (INK1117 and TAK-117) is an orally bioavailable, PI3K p110α- isoform-specific inhibitor with an in vitro IC50 of 15 nM, highly selective against other isoforms (p110β, p110γ, and p110δ) and mTOR (no significant inhibitions at 1 μM concentration). It displayed significant efficacy in several PI3Kα mutant-specific preclinical mouse xenograft tumor models, and blocked signaling to Akt and inhibited the growth of cancer cells harboring wild-type or mutated p110α. Preclinical studies showed TAK-117 to have the low potential for disrupting glucose metabolism or for causing cardiac adverse events; in rats and monkeys, doses up to 50 mg/kg/day were well tolerated. Serabelisib is currently under clinical evaluation.

Naquotinib (ASP8273) is an orally available, irreversible, mutant-selective, epidermal growth factor receptor (EGFR) inhibitor, with potential antineoplastic activity. Naquotinib was found by mass spectrometry to covalently bind to a mutant EGFR (L858R/ T790M) via cysteine residue 797 in the kinase domain of EGFR with long-lasting inhibition of EGFR phosphorylation for 24 h. In the NSCLC cell lines harboring the above EGFR mutations, Naquotinib had IC50 values of 8-33 nM toward EGFR mutants, more potently than that of WT EGFR (IC50 value of 230 nM). In mouse xenograft models, Naquotinib induced complete regression of the tumors after 14 days of treatment. ASP8273 even showed activity in mutant EGFR cell line which is resistant to other EGFR TKIs. Naquotinib is in phase III clinical trials for the oral treatment of EGFR mutated non-small cell lung cancer (NSCLC).

Sepantronium bromide (YM155) is a selective survivin suppressant that exhibits potent antitumor activities by inducing apoptosis and autophagy in various types of cancer. Sepantronium bromide inhibited the growth of various human cancer cell lines in vitro with GI50 values in the low nM range. Sepantronium bromide blocked the growth of 119 human cancer cell lines, with the greatest inhibition in lines derived from non-Hodgkin's lymphoma, hormone-refractory prostate cancer, ovarian cancer, sarcoma, non-small-cell lung cancer, breast cancer, leukemia, and melanoma, with an average GI50 of 15 nM. Sepantronium bromide inhibited the growth of tumor cell lines regardless of their p53 status and demonstrated significant antitumor activity in 5 mice xenograft models. It also caused tumor regressions in vivo, possibly by its effects in reducing intratumoral survivin expression levels and increasing apoptosis. Sepantronium Bromide had been in phase II clinical trials by Astellas for the treatment of prostate cancer, melanoma, non-Hodgkin's lymphoma, breast cancer, diffuse large B cell lymphoma, non-small cell lung cancer (NSCLC) and other solid tumors. This compound had also been in clinical trials by National Cancer Institute (NCI) for the treatment of solid tumors (phase I) and advanced non-small cell lung cancer (NSCLC) (phase II). However, all these researches about this compound for all indications were discontinued.

CUDC-101 is a multi-targeted agent designed to inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor Type 2 (Her2) and histone deacetylase (HDAC). This drug synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. Thus, a single compound may offer greater therapeutic benefits, which is verified in clinical trial phase I for the treatment patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer tumors. In April 2013, CURIS, INC determined that they would discontinue enrolling patients in phase 1 expansion trial of the intravenous formulation of CUDC-101, and that the future development of CUDC-101 would be dependent on our ability to successfully develop an oral formulation of CUDC-101. However, the efforts to develop an effective oral formulation with improved bioavailability have not resulted in significant improvements when compared to the intravenous formulation of CUDC-101. As a result, at this time CURIS no longer plan to make material investments in this program.

Gemcitabine elaidate is an ester of anticancer drug gemcitabine and elaidic fatty acid. The motivation to make an ester was to facilitate gemcitabine uptake and prolong retention in the cell. The drug is converted to parent compound gemcitabine both inside and outside the cell. Gemcitabine elaidate was developed by Clavis Pharma for treatment of solid tumors, including non-small cell lung cancer and pancreatic cancer, but its development was discontinued after product missed the primary endpoint in the Phase II LEAP trial to treat metastatic pancreatic cancer.

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.

LY-3009120 is an orally available inhibitor of all members of the serine/threonine protein kinase Raf family, including A-Raf, B-Raf, and C-Raf protein kinases, with potential antineoplastic activity. Upon administration, pan-RAF kinase inhibitor LY3009120 inhibits Raf-mediated signal transduction pathways, which may inhibit tumor cell growth. Raf protein kinases play a key role in the RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway, which is often dysregulated in human cancers and plays a key role in tumor cell proliferation and survival. LY3009120 is being investigated in phase I clinical trial.

Napabucasin (BBI608) is an orally administered small molecule that blocks stem cell activity in cancer cells by targeting the signal transducer and activator of transcription 3 pathway, which is over-activated in many types of cancer and has been shown to be an important pathway in cancer stem cell-mediated propagation of cancer. Napabucasin has already shown promising efficacy on different cancer types, both as a monotherapy and in combination with conventional chemotherapeutic agents. Early-phase trials have shown promising anti-tumor efficacy when patients are treated with napabucasin in combination with standard chemotherapy agents, and preclinical results suggest that napabucasin can synergize with chemotherapy agents, such as paclitaxel, to potentially overcome drug resistance. Encouraging phase Ib/II trial results warrant further clinical study with napabucasin and paclitaxel combination therapy, especially in malignancies where there is an urgent and unmet need for effective therapeutics, such as in patients with advanced pancreatic adenocarcinoma.

VTP-194204 (NRX 194204, IRX4204) is a second-generation retinoid X receptor (RXR) agonist that has no cross-reactivity with retinoic acid receptors, farnesoid X receptor, liver X receptors or peroxisome proliferator-activated receptor PPARγ. Rexinoid NRX 194204 selectively binds to and activates RXRs. Because RXRs can form heterodimers with several nuclear receptors (NRs), RXR activation by this agent may result in a broad range of gene expression depending on the effector DNA response elements activated. Rexinoid NRX 194204 may inhibit the tumour-necrosis factor (TNF)-mediated release of nitric oxide (NO) and interleukin 6 (IL6) and may inhibit tumour cell proliferation. This agent appears to be less toxic than RAR-selective ligands. VTP-194204 (IRX-4204) is in phase II clinical trials by Io Therapeutics for the treatment of prostate cancer. It is also in preclinical trials for the treatment of Alzheimer's disease, autoimmune diseases and multiple sclerosis.