Amuvatinib (formerly known as MP470) is an oral multi-targeted tyrosine kinase inhibitor, which play critical roles in transducing growth signals to cancer cells. It suppresses c-MET, c-RET and the mutant forms of cKIT, PDGFR and FLT3. It also disrupts DNA repair likely through suppression of homologous recombination protein Rad51, an important survival pathway in many human cancers. In vitro and in vivo data have demonstrated amuvatinib synergy with DNA damaging agents including etoposide and doxorubicin. Overall, in the amuvatinib clinical development program, over 200 subjects were exposed to at least one dose of amuvatinib. In the Phase 1b clinical study in combination with carboplatin and etoposide, responses in small cell lung cancer (SCLC), neuroendocrine as well as other tumor types were observed. Human pharmacokinetic data suggest that co-administration of amuvatinib did not alter exposures of standard of care agents including carboplatin, etoposide, doxorubicin, paclitaxel, topotecan or erlotinib as measured by overall exposure. In the first-in-human study, durable clinical benefit was observed in the gastrointestinal stromal tumors (GIST) with modulation of Rad51 observed in skin punch biopsies. In clinical trials, amuvatinib has demonstrated a wide therapeutic window and shows minimal toxicity in the expected therapeutic dose range, despite suppressing several signaling pathways within cells. However, in spite of this, this drug was discontinued, because it was not pre-specified primary endpoints in the clinical proof of concept (cPOC) stage. But the combination of MP470 and Erlotinib, which target the HER family/PI3K/Akt pathway may represent a novel therapeutic strategy for prostate cancer.

Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.

Halofuginone is a low molecular weight quinazolinone alkaloid, and a potent inhibitor of collagen alpha1(I) and matrix metalloproteinase 2 (MMP-2) gene expression. Halofuginone also effectively suppresses tumor progression and metastasis in mice. Halofuginone is a potent inhibitor of collagen a1(I) and matrix metalloproteinase 2 (MMP-2) gene expression. Halofuginone also suppresses extracellular matrix deposition and cell proliferation. Also was shown that halofuginone increased apoptosis in α smooth muscle actin- and prolyl 4-hydroxylase β-expressing cells in mdx diaphragm and in myofibroblasts, the major source of extracellular matrix. The profound antitumoral effect of halofuginone is attributed to its combined inhibition of tumour-stromal support, vascularization, invasiveness, and cell proliferation. HT-100 (delayed-release halofuginone), currently in clinical phase 1b/2a in five U.S. hospitals, is a small molecule drug candidate taken orally for the treatment of Duchenne muscular dystrophy (DMD) patients primarily through its ability to reduce fibrosis and inflammation and promote muscle fiber regeneration. The medicine candidate has been granted orphan drug designation in the U.S. and the EU — meaning it has been commercially undeveloped due to its limited profitability — and fast-track designation in the U.S. — an FDA process that aims to facilitate the development and patients’ reach to novel therapies for unmet medical needs.

IROFULVEN is a semisynthetic derivative of a natural sesquiterpene toxin illudin S, isolated from the fungus Omphalotus illudens. It alkylates DNA and protein macromolecules, forms adducts, and arrests cells in the S-phase of the cell cycle. It requires NADPH-dependent metabolism by alkenal/one oxidoreductase for activity. IROFULVEN is more active in vitro against tumor cells of epithelial origin and is more resistant to deactivation by p53 loss and P-glycoprotein than other alkylating agents. IROFULVEN has been evaluated in 19 clinical trials, predominantly in refractory prostate and ovarian cancer patients. Results were positive, including a 10% response rate in patients with prostate cancer previously treated with docetaxel and 13% in ovarian cancer patients relapsing between 6 and 12 months after standard treatment with carboplatin and paclitaxel.

RP6530 (Tenalisib) is a potent and selective dual Phosphatidylinositol 3 kinase (PI3K) δ/γ inhibitor. It inhibited growth of B-cell lymphoma cell lines, additionally, the compound showed cytotoxicity in a panel of lymphoma primary cells. Rhizen Pharmaceuticals is developing RP6530 for the treatment of hematologic malignancies.

Resiquimod is an imidazoquinolinamine and Toll-like receptor (TLR) agonist with potential immune response modifying activity. Resiquimod exerts its effect through the TLR signaling pathway by binding to and activating TLR7 and 8 mainly on dendritic cells, macrophages, and B-lymphocytes. This induces the nuclear translocation of the transcription activator NF-kB as well as activation of other transcription factors. This may lead to an increase in mRNA levels and subsequent production of cytokines, especially interferon-alpha (INF-a) and other cytokines, thereby enhancing T-helper 1 (Th1) immune responses. In addition, topical application of resiquimod appears to activate Langerhans' cells, leading to an enhanced activation of T-lymphocytes. Resiquimod is used as a topical gel[1] in the treatment of skin lesions[2] such as those caused by the herpes simplex virus[3][4] and cutaneous T cell lymphoma. Due to its immunostimulatory activity, this agent may potentially be used as a vaccine adjuvant.

Triapine (3-aminopyridine-2-carboxaldehyde thiosemcirbazone, (3-AP; NTO-1151; OCX-0191) is a novel small molecule ribonucleotide reductase inhibitor that acts on the M2 (R2) subunit. Ribonucleotide reductase is an enzyme involved in the de novo synthesis of deoxyribonucleotides, which are critical for DNA replication and DNA repair. Triapine has been used in trials phase II studying the treatment of Lung Cancer, Kidney Cancer, Prostate Cancer Pancreatic Cancer, among others. Recently was published the article describing, that the triple combination triapine-cisplatin-paclitaxel was safe and provided a rational basis for a follow-up phase II trial to evaluate the efficacy and progression-free survival in women with metastatic or recurrent uterine cervix cancer.

2-(1-Hexyloxyethyl)-2-devinyl pyropheophorbide-a (HPPH), a chlorin-based photosensitize, is used in photodynamic therapy. It has been shown the therapeutic potential of HPPH in phase II clinical trials for the treatment of esophageal cancer. Besides, HPPH participated in clinical trials in treating patients with advanced non-small cell lung cancer that blocks the air passages. However, these studies were terminated.

Lapachone (aka beta-Lapachone) is an ortho naphthoquinone, originally isolated from a tree whose extract has been used medicinally for centuries. It has garnered interest as a potential therapeutic or lead compound against a number of disease conditions including cancers, and blindness due to retinopathy of prematurity. It is lethal to a number of cancer cell types at micromolar concentrations, and it is capable of enhancing the efficacy of radiation therapies against cultured cells. A number of clinical trials have been conducted.