Reference Detail

Request Content

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type
PMID
Authors Andrew R. Conery; Artyom A. Alekseyenko; David Marcoux; Aaron G. Bart; Matt L. Harlow; Patrick R. Arsenault; Nico R. Cantone; Rebecca L. Casaubon; Hari B. Kamadurai; Aravind Prasad. Medikonda; Duncan E. Nunes; Vito J. Palombella; Kathleen I. Seyb; Tim J. Wigle; Maolin Yu; Aleksandra Zagulyaeva; Christine Zarate; Daniel S. La
Title Abstract B064: TRI-611, a selective, CNS-penetrant molecular glue degrader of ALK with anti-tumor activity against preclinical models of ALK-fusion positive non-small cell lung cancer including kinase inhibitor refractory tumors
Journal Vol Issue Date Pages Journal Short Title
Mol Cancer Ther 24 10_Supplement Mol Cancer Ther
URL https://aacrjournals.org/mct/article/24/10_Supplement/B064/766584/Abstract-B064-TRI-611-a-selective-CNS-penetrant
Abstract Text Therapeutic inhibition of Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase has transformed the treatment of ALK fusion-positive non-small cell lung carcinoma (NSCLC), but tyrosine kinase inhibitors (TKIs) are limited by toxicity, central nervous system (CNS) metastasis, and acquired resistance. Molecular glue degraders that eliminate disease drivers by engaging the ubiquitin/proteasome system are a promising alternative approach that may not be subject to the same liabilities as enzymatic inhibitors. Here we describe TRI-611, a potent, brain-penetrant molecular glue degrader that enables E3 ligase recognition of ALK via a degron that is distal from the orthosteric site of TKI binding. Using biochemical, biophysical, and cellular studies, we show that TRI-611 promotes the ubiquitination and degradation of ALK fusion alleles, including those with clinically relevant acquired TKI resistance mutations, and as a result has a broader phenotypic impact on ALK fusion-driven cell lines than ALK TKIs. TRI-611 is CNS penetrant and promotes tumor regression with daily oral dosing in both subcutaneous and intracranial models of ALK+ NSCLC. The distinct binding interface of TRI-611 leads to broad selectivity across the global proteome including closely related kinases such as NTRK1, allowing for sustained high target coverage, including in the CNS, without the off-target liabilities that are associated with TKIs. TRI-611 is currently in IND-enabling studies with the potential to transform the treatment of ALK+ NSCLC and would represent the first clinical stage molecular glue degrader of an oncogenic fusion protein.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
TRI-611 TRI-611 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
TRI-611 TRI 611|TRI611 TRI-611 is a CNS-penetrant small molecule targeting ALK for degradation, which may inhibit the growth of ALK-positive tumors (Mol Cancer Ther (2025) 24 (10_Supplement): B064).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK fusion lung non-small cell carcinoma predicted - sensitive TRI-611 Preclinical - Cell line xenograft Actionable In a preclinical study, TRI-611 treatment resulted in tumor regression in subcutaneous and intracranial cell line xenograft models of ALK fusion-positive non-small cell lung cancer (Mol Cancer Ther (2025) 24 (10_Supplement): B064). detail...