RO-5045337 (RG7112) is a small molecule that binds to a MDM2, a negative regulator of tumor-supressor protein p53. It was discovered by Roche and investigated in clinical trials against solid tumors, leukemias and sarcomas.

Amgen is developing AMG-900, an orally active, small molecule aurora kinase A, B and C inhibitor for the treatment of solid tumours and haematological malignancies. In tumor cells, AMG-900 inhibited autophosphorylation of aurora-A and -B as well as phosphorylation of histone H3 on Ser(10), a proximal substrate of aurora-B. The predominant cellular response of tumor cells to AMG-900 treatment was aborted cell division without a prolonged mitotic arrest, which ultimately resulted in cell death. AMG-900 inhibited the proliferation of 26 tumor cell lines, including cell lines resistant to the antimitotic drug paclitaxel and to other aurora kinase inhibitors (AZD1152, MK-0457, and PHA-739358), at low nanomolar concentrations. Furthermore, AMG-900 was active in an AZD1152-resistant HCT116 variant cell line that harbors an aurora-B mutation (W221L). Oral administration of AMG-900 blocked the phosphorylation of histone H3 in a dose-dependent manner and significantly inhibited the growth of HCT116 tumor xenografts. Importantly, AMG-900 was broadly active in multiple xenograft models, including 3 multidrug-resistant xenograft models, representing 5 tumor types. AMG-900 has entered clinical evaluation in adult patients with advanced cancers and has the potential to treat tumors refractory to anticancer drugs such as the taxanes.

MK-8776 (SCH900776) is inhibitor of CHK1. It was tested in clinical trials against acute myeloid leukaemia, solid tumors and lymphoma.

AZD-1208 is an orally available, potent and highly selective Pim inhibitor that effectively inhibits all three isoforms. AZD-1208 inhibits the growth of several AML cell lines and sensitivity correlates with the level of Pim-1 expression, STAT5 activation and presence of protein tyrosine kinase mutation. AZD-1208 causes cell cycle arrest and apoptosis in MOLM-16 cells in culture. This is accompanied by a dose-dependent reduction in phosphorylation of BAD, 4EBP1 and p70S6K. In addition, AZD-1208 leads to potent inhibition of colony growth of primary AML cells from bone marrow aspirates and downregulates phosphorylation of Pim targets. AZD-1208 was in Phase 1 trials to evaluate the safety and tolerability profile and to determine the maximum tolerated dose (MTD). There were two trials where AZD-1208 had been administered orally in AML and solid tumour (of all types) patients. The studies had being discontinued due to safety reasons.

I-BET-762 (GSK 525762) is a small molecule benzodiazepine, by 'mimicking' acetylated histones interferes with the recognition of acetylated histones by BET family of bromodomains (BRD2, BRD3, and BRD4), which disrupts chromatin remodeling and gene expression. Prevention of the expression of certain growth-promoting genes may lead to an inhibition of tumour cell growth. GlaxoSmithKline is developing GSK 525762 for the oral treatment of solid tumours and haematological malignancies.

Pevonedistat (MLN4924), discovered by Millennium, is a small molecule inhibitor of the NEDD8-Activating Enzyme (NAE), a key component of the protein homeostasis pathway. MLN4924 is a mechanism-based inhibitor of NAE and creates a covalent NEDD8-MLN4924 adduct catalyzed by the enzyme. The NEDD8-MLN4924 adduct resembles NEDD8 adenylate, the first intermediate in the NAE reaction cycle, but cannot be further utilized in subsequent intraenzyme reactions. The stability of the NEDD8-MLN4924 adduct within the NAE active site blocks enzyme activity, thereby accounting for the potent inhibition of the NEDD8 pathway by MLN4924. This drug is in phase II clinical trial for the treatment acute myeloid leukemia, chronic myelomonocytic leukemia and myelodysplastic syndromes. In addition in phase I for treatment acute lymphoblastic leukemia. The ability of MLN4924 to cross the blood-brain barrier, its low toxicity, and clinical efficacy in other cancers suggests that this drug is an attractive treatment against glioblastomas.

8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action remains poorly understood, however, it is known that the drug inhibits RNA synthesis. It has significant cytotoxic activity against lymphoid and myeloid malignant cells. The nucleoside analog 8-Cl-Ado is phosphorylated into its cytotoxic triphosphate 8-Cl-ATP. The accumulation of the cytotoxic metabolite results in a parallel decrease of the ATP cellular pools. 8-Cl-Ado gets incorporated into RNA during transcription, hindering this process. In addition, this triphosphate inhibits ATP-dependent poly(A) tail synthesis, and, as a consequence, mRNA processing is inhibited, resulting in vitro cytotoxicity in several solid and hematological malignancies. This agent is currently in clinical trials for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia.

Volasertib (BI 6727), a dihydropteridinone derivative, is a small-molecule cell cycle inhibitor of polo-like kinase-1 (PLK-1). Volasertib induces G2-M arrest and induction of apoptosis in cancer cells and potently inhibits tumor growth in xenograft models. Boehringer Ingelheim is developing intravenously administered volasertib for the treatment of acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), non-small cell lung cancer, urogenital cancer, ovarian cancer and solid tumours.

Ganetespib (formerly called STA-9090) is a novel, injectable resorcinolic triazolone small molecule inhibitor of Hsp90, developed by Synta Pharmaceuticals. Ganetespib inhibits the growth of many tumor types in vitro and in vivo including AML, ALL, CML, NHL, neuroblastoma, Ewing sarcoma, rhabdoid cancer, rhabdomyosarcoma, melanoma, and carcinomas of the breast, lung, prostate, bladder and colon7-10,14-27. Ganetespib has being studied in multiple adult oncology indications. The 50% inhibitory concentrations (IC50) for Ganetespib against malignant mast cell lines are 10-50 times lower than that for 17-AAG, indicating that triazolone class of HSP90 inhibitors likely exhibits greater potency than geldanamycin based inhibitors. Ganetespib inhibits MG63 cell lines with IC50 of 43 nM. Ganetespib binds to the ATP-binding domain at the N-terminus of Hsp90 and serves as a potent Hsp90 inhibitor by causing degradation of multiple oncogenic Hsp90 client proteins including HER2/neu, mutated EGFR, Akt, c-Kit, IGF-1R, PDGFRα, Jak1, Jak2, STAT3, STAT5, HIF-1α, CDC2 and c-Met as well as Wilms' tumor 1. Ganetespib, at low nanomolar concentrations, potently arrests cell proliferation and induces apoptosis in a wide variety of human cancer cell lines, including many receptor tyrosine kinase inhibitor- and tanespimycin-resistant cell lines. Ganetespib exhibits potent cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib has been studied in 5 completed Synta-sponsored clinical trials (Studies 9090-02, 9090-03, 9090-04, 9090-05, and 9090-07) and 3 completed Synta-sponsored studies in normal healthy volunteers (9090-12, 9090-13, and 9090-15). Ganetespib is currently being studied in 6 Synta-sponsored clinical trials. Studies include: one Phase 1 study, three Phase 2 studies, one Phase 2b study, and one Phase 3 study. Ganetespib is also being studied in 24 Investigator Sponsored Trials (ISTs)

Barasertib (AZD1152) is a dihydrogen phosphate prodrug of a pyrazoloquinazoline Aurora kinase inhibitor [AZD1152–hydroxyquinazoline pyrazol anilide (HQPA)] and is converted rapidly to the active AZD1152-HQPA in plasma. AstraZeneca was developing the aurora kinase inhibitor, barasertib (AZD 1152) as a therapeutic for cancer. AZD1152-HQPA is a highly potent and selective inhibitor of Aurora B (Ki, 0.36nmol/L) compared with Aurora A (Ki, 1,369nmol/L) and has a high specificity versus a panel of 50 other kinases. Consistent with inhibition of Aurora B kinase, addition of AZD1152-HQPA to tumour cells in vitro induces chromosome misalignment, prevents cell division, and consequently reduces cell viability and induces apoptosis. Barasertib (AZD1152) potently inhibited the growth of human colon, lung, and haematologic tumour xenografts (mean tumour growth inhibition range, 55% to ≥100%; P < 0.05) in immunodeficient mice. Detailed pharmacodynamic analysis in colorectal SW620 tumour-bearing athymic rats treated i.v. with Barasertib (AZD1152) revealed a temporal sequence of phenotypic events in tumours: transient suppression of histone H3 phosphorylation followed by accumulation of 4N DNA in cells (2.4-fold higher compared with controls) and then an increased proportion of polyploid cells (>4N DNA, 2.3-fold higher compared with controls). Histologic analysis showed aberrant cell division that was concurrent with an increase in apoptosis in AZD1152-treated tumours. Bone marrow analyses revealed transient myelosuppression with the drug that was fully reversible following cessation of Barasertib (AZD1152) treatment. Barasertib (AZD1152) was in phase III for the treatment of Acute myeloid leukaemia, but later these studies were discontinued.