An overview of the latest developments in PROTAC technology and the possible directions of this approach is presented.

The transforming growth factor beta (TGFβ) signaling cascade is considered as one of the pivotal oncogenic pathways in most advanced cancers. Inhibition of the TGFβ signaling pathway by specific antagonists, neutralizing antibodies, or small molecules is considered as an effective strategy for the treatment of tumor growth and metastasis. Here we demonstrated the identification of a series of tetrahydro-β-carboline derivatives from virtual screening which potentially inhibit the TGFβ signaling pathway. Optimization of the initial hit compound 2-benzoyl-1,3,4,9-tetrahydro-β-carboline (8a) through substitution at different positions to define the structure-activity relationship resulted in the discovery of potent inhibitors of the TGFβ signaling pathway. Among them, compound 8d, one of the tested compounds, not only showed potent inhibition of lung cancer cell proliferation and migration in vitro but also strongly suppressed growth of lung cancer and breast cancer in vivo.

Inhibition of angiogenesis is considered as one of the desirable pathways for the treatment of tumor growth and metastasis. Herein we demonstrated that a series of pyridinyl-thiazolyl carboxamide derivatives were designed, synthesized and examined against angiogenesis through a colony formation and migration assays of human umbilical vein endothelial cells (HUVECs) in vitro. A structure-activity relationship (SAR) study was carried out and optimization toward this series of compounds resulted in the discovery of N-(3-methoxyphenyl)-4-methyl-2-(2-propyl-4-pyridinyl)thiazole-5-carboxamide (3k). The results indicated that compound 3k showed similar or better effects compared to Vandetanib in suppressing HUVECs colony formation and migration as well as VEGF-induced angiogenesis in the aortic ring spreading model and chick embryo chorioallantoic membrane (CAM) model. More importantly, compound 3k also strongly blocked tumor growth with the dosage of 30 mg/kg/day, and subsequent mechanism exploration suggested that this series of compounds took effect mainly through angiogenesis signaling pathways. Together, these results suggested compound 3k may serve as a lead for a novel class of angiogenesis inhibitors for cancer treatments.

: Myoferlin (MYOF), as a member of the ferlin family, is a type II transmembrane protein with a single transmembrane domain at the carbon terminus. Studies have shown that MYOF is involved in pivotal physiological functions related to numerous cell membranes, such as extracellular secretion, endocytosis cycle, vesicle trafficking, membrane repair, membrane receptor recycling, and secreted protein efflux. Recently, the studies have also revealed that MYOF is overexpressed in a variety of cancers such as colorectal cancer, pancreatic cancer, breast cancer, melanoma, gastric cancer, and non-smallcell lung cancer. High expression of MYOF is associated with the high invasion of tumors and poor clinical prognosis. MYOF medicates the expression, secretion, and distribution of proteins which were closely related to cancers, as well as the energy utilization of cancer cells, lipid metabolism and other physiological activities by regulating the physiological processes of membrane transport. In this short article, we briefly summarize the latest progress related to MYOF, indicating that small molecule inhibitors targeting MYOF-C2D domain can selectively inhibit the proliferation and migration of cancer cells, and MYOF may be a promising target for the treatment of malignant tumors.