MS4077 is a potent PROTAC degrader of anaplastic lymphoma kinase (ALK) with a Kd of 37 nM for binding affinity to ALK. MS4077 and MS4078 potently decreased 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 compounds 5 and 6 was cereblon and proteasome dependent. In addition, MS4077 and MS4078 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. This study paved the way for developing the next generation of ALK PROTACs.