TRI-611, a development stage molecular glue degrader of ALK for the treatment of ALK-positive NSCLC including central nervous system metastases

Therapeutic inhibition of Anaplastic Lymphoma Kinase (ALK) has transformed the treatment of ALK fusion-positive non-small cell lung carcinoma (NSCLC), but ALK tyrosine kinase inhibitors (TKIs) suffer from liabilities common to all orthosteric inhibitors, such as off-target kinase inhibition and resistance alleles in and around the TKI binding site. Molecular glue degraders (MGDs) that engage the CRL4 CRBN E3 ligase to promote neosubstrate degradation offer an alternative therapeutic approach. Here we describe TRI-611, a potent, brain-penetrant MGD that promotes the proximity of ALK and CRBN via a unique, non-G loop degron interface that is distal from the kinase active site. TRI-611 functions by engaging CRBN to create a neosurface that interacts with the C-lobe of the ALK kinase domain. This ALK:TRI-611:CRBN ternary complex promotes ALK polyubiquitination and CRBN-dependent degradation of ALK proteins, including ALK fusions such as EML4-ALK, and oncogenic, transmembrane ALK. Cellular degradation of EML4-ALK is rapid (occurring within 1-2 hours), robust (>90% maximum degradation), and durable (recovery half-life of more than 15 hours after compound withdrawal). Cellular proteomics profiling demonstrates the profound selectivity of TRI-611 across CRBN neosubstrates and the kinome (including key off-target kinase families such as NTRK), consistent with the unique degron interface located in a less conserved region of ALK. TRI-611 treatment leads to inhibition of downstream signaling and subsequent selective anti-proliferation of ALK-positive cell lines. TRI-611 is orally bioavailable and brain penetrant, with daily oral dosing leading to deep and durable degradation of endogenous EML4-ALK and tumor regression in both subcutaneous and intracranial xenograft models of ALK-positive NSCLC. TRI-611 represents the first example of a development stage degrader targeting an oncogenic gene fusion and has the potential to expand the arsenal of meaningful therapeutic options for ALK-positive NSCLC patients. The discovery of TRI-611 additionally broadens the reach of CRBN-modulating MGDs by exploiting a previously undescribed degron.