Tesevatinib (EXEL-7647 or XL647) was optimized as an inhibitor of a spectrum of growth-promoting and angiogenic receptor tyrosine kinases (RTKs) to simultaneously block tumor growth and vascularization. In particular, Tesevatinib potently inhibits the EGF/ErbB2, VEGF, and ephrin RTK families. The drug is being developed by Kadmon Corporation under licence from Symphony Evolution (Symphony Capital Partners). Kadmon is developing tesevatinib for the treatment of autosomal polycystic kidney disease and solid cancers.

SU-14813 is an oral, multitargeted tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptors (VEGFR), platelet-derived growth factor receptors (PDGFR), KIT, and fms-like tyrosine kinase 3 (FLT-3). SU-14813 was developed as a next-generation TKI agent following sunitinib (SU-11248) designed to demonstrate optimized pharmacokinetic (PK) and tolerability profiles. SU14813 demonstrated broad and potent antitumor activity equivalent to that of sunitinib, which resulted in tumor regression, growth arrest, growth delay, and prolonged survival in established xenograft cancer models in mice. A phase II trial of SU-14813 in patients with breast cancer was completed. However, according to the Pfizer pipeline development has been discontinued.

LY-3000328 is a Cathepsin S inhibitor with excellent in vitro potency and selectivity against other cysteine proteases. LY-3000328 is currently in clinical trials. Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cathepsin S may provide a new treatment for AAA.

CGM-097, a novel, highly optimized, and selective inhibitor of the p53-Mdm2 interaction. CGM-097 binds to human Mdm2 protein with a Ki value of 1.3 nM, activates p53 in human cells and induces robust p53-dependent cell cycle arrest and apoptosis in human p53 wild-type tumor cells. Its activity and selectivity has been tested and confirmed across a large panel of cancer cell lines from the Cancer Cell Line Encyclopedia. CGM-097 displays desirable pharmacokinetic and pharmacodynamic profiles in animals together with excellent oral bioavailability, which triggers rapid and sustained activation of p53-dependent pharmacodynamic biomarkers resulting in tumor regression in multiple xenografted models of p53 wild-type human cancer. The validation and understanding of its mechanism of action, the overall favorable drug-like properties and the characterization of its on-target toxicological profile in preclinical species strongly supported the initiation of Phase I clinical trials with CGM-097 in pre-selected patients with p53 wild-type tumors.

TAS-116 is a highly potent oral HSP90 inhibitor with unique tissue distribution properties. TAS-116 has the potential to demonstrate antitumor activity, while being designed to limit certain adverse events by unique tissue distribution. Phase-II clinical trials in gastrointestinal stromal tumours are ongoing in Japan.

DS-3032 (Milademetan) is an orally available, potent and selective inhibitor of the p53-MDM2 (murine double minute 2) interaction. Milademetan binds to, and prevents the binding of MDM2 protein to the transcriptional activation domain of the tumor suppressor protein p53. Milademetan is 10-fold more potent than the first-generation inhibitor nutlin-3a. By preventing this MDM2-p53 interaction, the proteasome-mediated enzymatic degradation of p53 is inhibited and the transcriptional activity of p53 is restored. This results in the restoration of p53 signaling and leads to the p53-mediated induction of tumor cell apoptosis. DS-3032 is currently being evaluated in three phase 1 clinical trials for solid and hematological malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) in blast phase, lymphoma and myelodysplastic syndrome (MDS).

Lifirafenib (BGB-283 or BEIGENE-283), a dual inhibitor targeting BRAF kinase and EGFR, was studied for the treatment of different cancer types harboring mutations in BRAF, KRAS, and NRAS. Lifirafenib participates in Phase II clinical trial in combination with PD-0325901 to treat the patients with solid tumor.