MS4077 is an Anaplastic Lymphoma Kinase PROTAC (Degrader)
Posted On 2019-05-19
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, which belongs to the insulin receptor kinase subfamily. ALK correlates with oncogenesis in different types of cancers, such as anaplastic large-cell non-Hodgkin’s lymphoma (ALCL), non-small-cell lung cancer (NSCLC), squamous cell carcinoma (SCC), renal cell carcinoma (RCC), thyroid cancer, breast cancer, colon carcinoma, lung cancer, ovarian cancer, neuroblastoma, and so on. Especially, ALK activates multiple pathways. These include JAK-STAT, PI3K-AKT, mTOR, sonic hedgehog and MAPK signaling cascades, which affect cell growth, transformation and anti-apoptotic signaling. ALK is the product of a gene rearrangement in anaplastic large cell lymphoma (ALCL). The emerging Proteolysis Targeting Chimera (PROTAC) technology applies to selective degradation of multiple protein targets. In particular, ALK is an ideal target for developing PROTACs. Moreover, ALK expresses throughout the nervous system during embryogenesis predominantly and its expression is very low in normal adult tissues.
In this study, ChengweiZhang, et al reported the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 is an anaplastic lymphoma kinase (ALK) PROTAC degrader with a Kd of 37 nM for binding affinity to ALK. Moreover, MS4077 potently decreases cellular levels of oncogenic active ALK fusion proteins in a concentration and time dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by MS4077 is cereblon and proteasome dependent. In addition, MS4077 potently inhibits proliferation of SU-DHL-1 cells. In conclusion, MS4077 is a novel and potent ALK PROTAC (degrader).
Zhang C, et al. Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). Eur J Med Chem. 2018 May 10;151:304-314.