Tomivosertib (eFT-508) is a dual inhibitor of MAP kinase-interacting kinases (MNK1 and MNK2) thereby controlling translation. It has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors. Tomivosertib acts on multiple points in the cancer immunity cycle simultaneously, underscoring its therapeutic potential as both a monotherapy and in combination with existing checkpoint inhibitor treatments. Preclinical studies suggest combining tomivosertib with a checkpoint inhibitor can overcome mechanisms of resistance to checkpoint inhibitors, resulting in enhanced sensitivity to checkpoint inhibitors and a higher response rate. In addition, preclinical data demonstrate that tomivosertib as a single agent promotes antitumor immunity that persists after stopping drug treatment. Tomivosertib is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Additionally, tomivosertib may be a new therapeutic for neuropathic pain.

BAY-86-9596 (D-18F-FMT, or O-18F-fluoromethyl-D-tyrosine) was developed as an agent not only for tumor detection but also for monitoring early-phase response to radiation therapy by positron emission tomography (PET). This drug participated in clinical trials for patients with inflammation and solid tumors, but further information about trials is not available.

AZD3839 is a potent and selective BACE1 inhibitor with about 14-fold selectivity over BACE2. In SH-SY5Y cells, AZD3839 efficiently decreases the Aβ40 levels and decreases the formation of sAPPβ. AZD3839 also decreases the Aβ40 levels secreted from C57BL/6 mouse primary cortical neurons, N2A cells, and Dunkin-Hartley guinea pig primary cortical neurons. AZD3839 causes in vitro BACE1 inhibition in the cell assay with the IC50 value of 16.7 nM. In C57BL/6 mice, AZD3839 (69 mg/kg, p.o.) causes a dose- and time-dependent reduction of plasma and brain Aβ. In guinea pig and non-human primates, AZD3839 also inhibits Aβ generation. AZD3839 has been used in phase I clinical trials studying the basic science of Safety and Tolerability. However future development has been discontinued.

Idasanutlin (RG-7388) is a second-generation, orally bioavailable, selective p53-MDM2 antagonist. MDM2 is an important negative regulator of the p 53 tumor suppressor and is expressed at high levels in a large proportion of acute myeloid leukemia (AML). Blocking the MDM2-p53 interaction stabilizes p53 and activates p-53 mediated cell death and inhibition cell growth. Idasanutlin is under clinical trial in phase III for treatment AML and in combinations with others drugs in phase I/II for treatment of multiple myeloma.

APR-246 is a methylated form of PRIMA-1, 2-hydroxymethyl-2-methoxymethyl-aza-bicyclo[2.2.2]octan-3-one (PRIMA-1MET). APR-246, is a prodrug that is converted to the Michael acceptor methylene quinuclidinone (MQ) that binds covalently to cysteines in p53, leading to refolding and restoration of wild type p53 function. MQ also targets the cellular redox balance by inhibiting thioredoxin reductase (TrxR1) and depleting glutathione. APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. APR-246 has demonstrated compelling pre-clinical antitumor activity in a wide variety of solid and hematological (blood) tumors, including ovarian cancer, small cell lung cancer, esophageal cancer and acute myeloid leukemia (AML), among others. Furthermore, strong synergy has been seen with both traditional anticancer agents, such as chemotherapy, as well as newer mechanism-based anticancer drugs. A Phase I clinical study has been completed, demonstrating a favorable safety profile and both biological and clinical responses in hematological tumors with mutations in the p53 gene. A Phase Ib clinical study in combination with full dose chemotherapy (carboplatin and pegylated liposomal doxorubicin) has also been completed, demonstrating a favorable safety profile in patients with high-grade serous ovarian cancer (HGSOC). APR-246 is currently in a Phase II clinical trial in patients with HGSOC, and additional Phase Ib clinical studies of APR-246 in other cancer indications are planned.