Donafenib (CM-4307) is a derivative of sorafenib, where [1H] hydrogens on the terminal methyl group are substituted by deuterium. The drug was developed by the Chinese company Suzhou Zelgen Biopharmaceuticals. Upon oral administration, donafenib binds to and blocks the activity of Raf kinase, and inhibits Raf-mediated signal transduction pathways. This inhibits cell proliferation in Raf-expressing tumor cells. In addition, donafenib may inhibit unidentified RTKs, and thus may further block tumor cell proliferation in susceptible tumor cells. Donafenib is being investigated in phase 3 clinical trials for the treatment of 131I-refractory differentiated thyroid cancer, advanced hepatocellular carcinoma, and metastatic colorectal cancer.

Entospletinib (GS-9973) is an adenosine triphosphate competitive inhibitor of Syk that disrupts kinase activity, which is currently in clinical trials for multiple B-cell malignancies. The most common treatment-emergent serious adverse events included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia.

Glesatinib (MGCD265) is an orally bioavailable, small-molecule, multitargeted tyrosine kinase inhibitor with potential antineoplastic activity. Glesatinib binds to and inhibits the phosphorylation of several receptor tyrosine kinases (RTKs), including the c-Met receptor (hepatocyte growth factor receptor); the Tek/Tie-2 receptor; vascular endothelial growth factor receptor (VEGFR) types 1, 2, and 3; and the macrophage-stimulating 1 receptor (MST1R or RON). Inhibition of these RTKs and their downstream signaling pathways may result in the inhibition of tumor angiogenesis and tumor cell proliferation in tumors overexpressing these RTKs. Studies in a gastric cancer xenograft model revealed that, in addition to the typically reported cellular activities, glesatinib in combination with erlotinib disrupted the glycolysis pathway, suggesting a novel mechanism of action for this drug. Glesatinib has been studied in a variety of advanced solid tumors including NSCLC, as a monotherapy and in combination with either docetaxel or erlotinib. In an ongoing phase 1 study in patients with MET positive or AXL-rearranged advanced solid tumors, glesatinib demonstrated preliminary single-agent activity, with all three patients with MET dysregulated NSCLC (two with METex14 alterations and one with increased GCN) showing significant tumor regression at the first assessment. A phase 2 study is currently recruiting patients with MET-dysregulated (mutated or amplified) advanced or metastatic NSCLC.

Derazantinib (ARQ 087) is an investigational, oral, multi-kinase inhibitor designed to preferentially inhibit the FGFR family of kinases with demonstrated activity in FGFR2 genetic alterations, including fusions. In human cancers, FGFRs have been found to be dysregulated by multiple mechanisms, including aberrant expression, mutations, chromosomal rearrangements, and amplifications. FGFR dysregulation has been identified as a driver in a number of cancers, including iCCA, cholangiocarcinoma, bladder, endometrial, breast, gastric, lung and ovarian. Current scientific literature suggests FGFR alterations exist in anywhere from 5% to 40% of these cancers. Derazantinib is a potent FGFR inhibitor that shows strong anti-proliferative activity in cell lines harboring FGFR2 alterations. In clinical testing, the molecule has demonstrated activity in cancerous tumors harboring FGFR2 fusions in iCCA and bladder cancers.

Sitravatinib (MGCD516) is a receptor tyrosine kinases (RTK) inhibitor that blocks a wide array of RTKs known to be amplified/overexpressed in sarcomas, which are key regulators of signaling pathways that lead to cell growth, survival and tumor progression. It is involved in driving sarcoma cell growth with IC50 of 3980 nM and is superior to other multi-kinase inhibitors in inhibiting cell proliferation, RTK phosphorylation, and phosphorylation of downstream effectors. The efficacy of sitravatinib was tested using a wide panel of sarcoma cell lines, including malignant peripheral nerve sheath tumor (MPNST), Ewing sarcoma (A673), osteosarcoma (Saos2), and liposarcoma (DDLS, LS141). Both in vitro and in vivo efficacy sitravatinib was significantly better that the other two multi-kinase inhibitors, imatinib and crizotinib. Sitravatinib treatment not only inhibits tumor cell proliferation at low nanomolar concentrations in vitro but also results significant tumor growth suppression in vivo in mouse xenograft models. Sitravatinib is being evaluated in a Phase 1b dose expansion cohort in selected patients with specific genetic alterations that are drivers of tumor growth, with an initial focus on Non-Small-Cell Lung carcinoma (NSCLC) and in other solid tumors where sitravatinib may confer a benefit. Its efficacy and safety is also being tested in Phase II clinical trials in patients with advanced liposarcoma as a monotherapy and NSCLC in combination with nivolumab.

Altiratinib, a novel c-MET/TIE-2/VEGFR inhibitor, was able to effectively reduce tumor burden in vivo and block c-MET signaling, cell growth and migration. Altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases. It is currently in Phase 1 clinical development for the treatment of solid tumors.

Tirabrutinib (also known as ONO-4059 or GS-4059), a second-generation, enhanced-selectivity Bruton's tyrosine kinase inhibitor that demonstrated antitumor activity in preclinical models. Tirabrutinib participated in phase I clinical trial in patients with relapsed or refractory B-cell malignancies, where it was well tolerated and showed promising efficacy. In addition, tirabrutinib is involved in phase II clinical trials to study safety and efficacy in adults with Active Sjogren's syndrome and in adults with chronic lymphocytic leukemia. Besides the drug was studied for the treatment of Waldenstrom's macroglobulinemia and patients with refractory pemphigus.

PF-06747775 is an irreversible pyrrolopyrimidine inhibitor of epidermal growth factor receptor (EGFR) T790M mutants which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. The third-generation class of EGFR tyrosine kinase inhibitors PF-06747775 is a clinical candidate drug for treatment of non-small-cell lung cancer (NSCLC) driven by mutant EGFR.