p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is currently in clinical trials. Based on X-ray cocrystal structures a model of AMG 232 bound to MDM2 was developed. The model shows that the m-chlorophenyl, the p-chlorophenyl, and C-linked isopropyl fragments of AMG 232 bind to the Leu 26(p53), Trp 23(p53), and Phe 19(p53) pockets of MDM2, respectively. The carboxylic acid forms a salt bridge with His 96 and the isopropyl sulfone forms a novel interaction with the glycine shelf region of MDM2. AMG 232 in phase II in combination with trametinib and dabrafenib in subjects with metastatic melanoma; in phase I for the treatment of solid tumors, multiple myeloma and Acute Myeloid Leukemia.

Uprosertib is an oral potent Akt inhibitor which acts equally on Akt1, Akt2 and Akt3. The drug is under clinical development in combination with trametinib for the treatment of different cancers, including melanoma, myeloma, breast, endometrial, cervical cancer, etc.

Luminespib (NVP-AUY922) is a highly potent isoxazole-based, nongeldanamycin HSP90 inhibitor that inhibits the adenosine triphosphatase activity of HSP90. Luminespib is a highly potent HSP90 inhibitor for HSP90α/β with IC50 of 13 nM /21 nM in cell-free assays, weaker potency against the HSP90 family members GRP94 and TRAP-1, exhibits the tightest binding of any small-molecule HSP90 ligand. Luminespib potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 less than 100 nM. IC100 value less than 40 nM was seen in 36 of 41 lines. Luminespib (NVP-AUY922) has greater potency, reduced hepatotoxicity, and lower dependence on DT-diaphorase than the first-generation HSP90 inhibitors. Luminespib was discovered in a multiparameter lead optimization program based on a high-throughput screening hit methodology developed jointly by The Institute of Cancer Research, UK and the pharmaceutical company Vernalis. It has been licensed to Novartis. Luminespib activity is independent of NQO1/DT-diaphorase, maintained in drug-resistant cells and under hypoxic conditions. The molecular signature of HSP90 inhibition, comprising induced HSP72 and depleted client proteins, was readily demonstrable. Pre-clinical studies proved that Luminespib acts via several processes (cytostasis, apoptosis, invasion, and angiogenesis) to inhibit tumor growth and metastasis. These results helped Luminespib to enter clinical trials for various cancers including breast cancers. From 2011 to 2014 it was in Phase II clinical trials.

AT7519M or AT7519, a small molecule inhibitor of cyclin-dependent kinases 1, 2, 4, 5, and 9, participated in phase II clinical trials in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). As a result, in CLL, some patients had tumor reductions, but the objective response rate (ORR) was low. In MCL, activity was noted with ORR of 27%. In addition, AT7519M was studied in patients with previously treated multiple myeloma, to understand whether the drug alone or in combination with bortezomib were effective treatments. Recent experiments also have shown that AT7519 is a promising drug for the treatment of high-risk neuroblastoma patients with MYCN amplification. It is known, that MYCN-dependent neuroblastomas have low cure rates with current multimodal treatment.

SNX-5422 (also known as PF-04929113) is a synthetic, novel, small molecule Hsp90 inhibitor with potential antineoplastic activity. Hsp90 is a molecular chaperone that plays a key role in the conformational maturation of oncogenic signaling proteins, such as HER2/ERBB2, AKT, RAF1, BCR-ABL, and mutated p53, as well as many other molecules that are important in cell cycle regulation or immune responses. Inhibition of Hsp90 by SNX-2112 may result in the proteasome degradation of oncogenic client proteins, including HER2/ERBB2, and the inhibition of tumor cell proliferation. SNX-5422 is originally developed by Pfizer and Serenex, Inc., and the phase I clinical trials for it has been completed in the treatment of solid tumors. Although the mechanism of action remains to be fully elucidated, SNX-5422, which is a prodrug, is rapidly converted to SNX-2112 that accumulates in tumors relative to normal tissues.

Oprozomib (PR-047) is an orally bioavailable derivative of carfilzomib, with similar biological activity, i.e. inhibition of the chymotrypsin-like activity of the proteasome. It inhibits the activity of the proteasome, thereby blocking the targeted proteolysis normally performed by the proteasome; this may result in an accumulation of unwanted or misfolded proteins. Disruption of various cell signaling pathways may follow, eventually leading to the induction of apoptosis and inhibition of tumor growth. Oprozomib (PR-047) is being investigated for the treatment of hematologic malignancies, specifically, multiple myeloma, with Phase I/II trial ongoing.

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.

KW-2478 is a novel and potent non-ansamycin inhibitor of heat shock protein 90 designed to overcome the limitations, including low water solubility and hepatotoxicity, of 17-allylamino-17-demethoxygeldanamycin (17-AAG). KW-2478 exerts a strong antitumor activity against multiple myeloma (MM) cells with various chromosomal translocations. KW-2478 inhibits cell growth and apoptosis associated with Hsp90 client protein degradation. Recent study results have revealed that KW-2478 is able to deplete Hsp90 client Cdk9 and the phosphorylated 4E-BP1, a transcriptional kinase and a transcription inhibitor respectively, leading to reduced expression of FGFR3, c-Maf, and cyclin D1. KW-2478 suppresses tumor growth and induces the degradation of client proteins in tumors in NCI-H929 s.c. inoculated model at doses of 100 mg/kg or more. KW-2478 reduces both serum M protein and MM tumor burden in the bone marrow in OPM-2/GFP i.v. inoculated mouse model at doses of 100 mg/kg.

Delanzomib (CEP-18770), a proteasome inhibitor, was being developed by Cepahlon (a subsidiary of Teva) for the treatment of cancer and immunological disorders. Delanzomib (CEP-18770) induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, Delanzomib (CEP-18770) has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Delanzomib represses the proteasomal degradation of a variety of proteins, including inhibitory kappaBalpha (IkappaBalpha), resulting in the cytoplasmic sequestration of the transcription factor NF-kappaB; inhibition of NF-kappaB nuclear translocation and transcriptional up-regulation of a variety of cell growth-promoting factors; and apoptotic cell death in susceptible tumor cell populations. In vitro studies indicate that this agent exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells relative to the proteasome inhibitor bortezomib. Delanzomib has been in phase II clinical trials for the treatment of multiple myeloma (MM). However, this research has been discontinued. Currently Delanzomib is on Phase I clinical trial for Non-Hodgkin's lymphoma and Solid tumours.

ABC-294640 is an orally bioavailable and selective sphingosine kinase-2 (SphK2) inhibitor with IC50 of approximately 60 uM. ABC-294640 inhibits SK2, a lipid kinase that catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including TNFα signaling and other inflammatory cytokine production. Specifically, by inhibiting the SK2 enzyme, ABC-294640 blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and are also involved in immune-modulation and suppression of innate immune responses from T cells. Preliminary evidence suggests that because of its specificity for targeting SK2, rather than SK1, ABC-294640 may have a better therapeutic ratio than nonspecific sphingosine kinase inhibitors or those targeting only SK1. Oral administration of ABC-294640 to mice bearing mammary adenocarcinoma xenografts results in dose-dependent antitumor activity associated with depletion of S1P levels in the tumors and progressive tumor cell apoptosis. Therefore, this newly developed SK2 inhibitor provides an orally available drug candidate for the treatment of cancer and other diseases. ABC-294640 has completed multiple successful pre-clinical studies in inflammatory, GI, radioprotection and oncology models, as well as a Phase I clinical study in cancer patients with advanced solid tumors.