TIC10 (TIC10 isomer or ONC201 isomer) is a potent, orally active, and stable small molecule and is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The isomeric structure of TIC10/ONC201 is critical to its activity: anti-cancer activity is associated with the angular structure and not the linear TIC10 isomer. TIC10 transcriptionally induces a sustained up-regulation TRAIL in tumors and normal cells in a p53-independent manner. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 crosses the blood-brain barrier. TIC10 treatment caused tumor regression in the HCT116 p53−/− xenograft, RKO human colon cancer xenograft–bearing mice and human triple-negative breast cancer xenografts and significantly prolonged the survival of Eμ-myc transgenic mice, which spontaneously develop metastatic lymphoma from weeks 9 to 12 of age by 4 weeks.

TAK-243 (MLN7243) is a small molecule inhibitor of ubiquitin-activating enzyme (UAE), with potential antineoplastic activity, which was developed by Takeda Oncology, Millennium. MLN7243 binds to and inhibits UAE, which prevents both protein ubiquitination and subsequent protein degradation by the proteasome. This inhibits tumor cell proliferation and survival. UAE, also called ubiquitin E1 enzyme (UBA1; E1), is more active in cancer cells than in normal, healthy cells. Currently, TAK-243 is in phase I clinical trial evaluating safety, tolerability, pharmacokinetics, pharmacodynamics against advanced malignant solid tumors phase.

A-443654 is a potent and selective AKT inhibitor. A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. A-443654 interferes with mitotic progression by regulating aurora a kinase expression. A-443654 inhibits all three Akt isoforms in FL5.12 cells stably transfected with constitutively active myristoylated Akt1/2/3, and showed moderate selectivity when screened against related kinases in the AGC family, such as PKA and PKC20. A-443654 has being shown to extend survival in an intracranial glioma animal model. A-443654, either alone or in combination with existing drugs, may be a useful therapy for primary and drug-resistant T-ALL.