Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase. ALK is an attractive target for cancer therapies not only for its prominent role in a number of malignancies but also for its scant expression in normal adult tissue. Therapeutic strategies that target ALK may provide ways to further delay the emergence of resistance mutations. PROTACs are hetero-bifunctional small molecules. PROTACs can induce degradation of a protein by bringing it into proximity of an E3 ligase. Especially, TL13-12 is a potent and selective PROTAC ALK degrader.
In this study, researchers designed the degrader TL13-12 based on known ALK inhibitor TAE684 and used the cereblon ligand Pomalidomide to recruit the E3 ubiquitin ligase complex. TL13-12 can induce ALK degradation in NSCLC cells expressing the fusion protein echinoderm microtubule-associated protein-like 4 (EML4)-ALK, ALCL cells expressing the fusion protein nucleophosmin (NPM)-ALK, and NB cells expressing either ALK F1174L or ALK R1275Q. Moreover, TL13-12 induces potent ALK degradation in Karpas 299 with the DC50 of 180 nM. In Kelly cells, TL13-12 is an ALK degrader with a DC50 of 50 nM. In H3122 cells, TL13-12 inhibits downstream signaling to a similar extent as its parental kinase inhibitor. When observing downstream signaling over a 48-hour time course in H3122 cells, TL13-12 sustains inhibition of ALK and STAT3 phosphorylation to a similar extent as TAE684.
To summarise, by linking ALK inhibitor TAE684 to Pomalidomide, TL13-12 displays the ability to improve upon the pharmacodynamic properties of their parental inhibitors, especially sustained inhibition of downstream ALK signaling. TL13-12 may be a promising new avenue for targeted ALK therapies.