CC-220 is a potent cereblon modulating agent that displays anti-proliferative, pro-apoptotic and immunomodulatory activity on sensitive and resistant multiple myeloma cell lines. CC-220 is currently under clinical investigation for systemic lupus erythematosus and multiple myeloma as a single agent, or in combination with dexamethasone in patients who may have previously been exposed to pomalidomide. Comparable to other Cereblon-binding agents, ex vivo treatment of CC-220 on B-cells, T-cells, and monocytes leads to the degradation of the hematopoietic transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). followed by disruption of the multiple myeloma promoting c-Myc/IRF4 axis.

PM-060184 is a new type of marine polyketide isolated from the Madagascan sponge. PM060184 belongs to a new family of tubulin-binding agents. PM060184 is an inhibitor of tubulin polymerization that reduces microtubule dynamicity in cells by 59%. Interestingly, PM060184 suppresses microtubule shortening and growing at a similar extent. PM060184 is able to overcome P-gp mediated resistance in vivo, an effect that could be related to its high binding affinity for tubulin. PM-060184 demonstrated antimitotic properties in human tumor cells lines at subnanomolar concentrations and display a distinct inhibition mechanism on microtubules. An antivascular mechanism is contributing to the antitumor activities of plocabulin. PM-060184 I in phase II clinical trial for the treatment of breast and colorectal cancer.

GLPG-0492, an orally available selective androgen receptor modulator (SARM) was tested in a Phase I Proof of Mechanism study to assess the effect on muscle function in healthy volunteers. A biomarker effect similar to that of Oxandrolone was observed, but the data were insufficient for Galapagos to pursue GLPG-0492 further in cachexia, and further development of the compound was discontinued. GLPG-0492 is currently under development for musculo-skeletal diseases such as sarcopenia and Duchenne muscular dystrophy.

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.