Dark Mode Light Mode
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.
Join us on a journey where chemistry meets creativity, and the wonders of science unfold. Quench your intellectual thirst with thought-provoking articles that transcend the boundaries of conventional knowledge.

TRI-611, a selective, brain-penetrant molecular glue degrader of ALK

TRI-611, a selective, brain-penetrant molecular glue degrader of ALK TRI-611, a selective, brain-penetrant molecular glue degrader of ALK


  • Schneider, J. L., Lin, J. J. & Shaw, A. T. ALK-positive lung cancer: a moving target. Nat Cancer 4, 330–343 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Voena, C., Ambrogio, C., Iannelli, F. & Chiarle, R. ALK in cancer: from function to therapeutic targeting. Nat. Rev. Cancer 25, 359–378 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shaw, A. T. et al. Lorlatinib versus crizotinib as first-line treatment for advanced ALK-positive non-small-cell lung cancer: 7-year update from the phase III CROWN study. Ann. Oncol. https://doi.org/10.1016/j.annonc.2026.05.692 (2026).

  • Saifudeen, M. et al. Comprehensive profiling of clinically approved kinase inhibitors reveals mutation-specific inhibitors and opportunities for drug repurposing. Nat. Biotechnol. https://doi.org/10.1038/s41587-026-03090-8 (2026).

  • Yoda, S. et al. Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-positive lung cancer. Cancer Discov. 8, 714–729 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Igawa, Y. et al. Association between lorlatinib blood concentration and adverse events and clinical impact of dose modification. Lung Cancer 196, 107954 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gao, Y. et al. Catalytic degraders effectively address kinase site mutations in EML4-ALK oncogenic fusions. J. Med. Chem. 66, 5524–5535 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kang, C. H. et al. Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC). Biochem. Biophys. Res. Commun. 505, 542–547 (2018).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, X. et al. A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance. iScience 27, 109015 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ren, C. et al. Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from alectinib. Eur. J. Med. Chem. 217, 113335 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sun, N. et al. Development of a brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance. Eur. J. Med. Chem. 193, 112190 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yan, G. et al. Discovery of a PROTAC targeting ALK with in vivo activity. Eur. J. Med. Chem. 212, 113150 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, C. et al. Proteolysis targeting chimeras (PROTACs) of anaplastic lymphoma kinase (ALK). Eur. J. Med. Chem. 151, 304–314 (2018).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • La, D. S., Nasveschuk, C. G. & Gilbert, A. M. in 2025 Medicinal Chemistry Reviews Medicinal Chemistry Reviews (eds Rudolph, J. & Watkins, W.) 399–427 (ACS, 2025).

  • Kozicka, Z. & Thoma, N. H. Haven’t got a glue: protein surface variation for the design of molecular glue degraders. Cell Chem. Biol 28, 1032–1047 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vetma, V., O’Connor, S. & Ciulli, A. Development of PROTAC degrader drugs for cancer. Annual Rev. Cancer Biol. 9, 119–140 (2025).

    Article 

    Google Scholar
     

  • Agarwal, P., Reid, D. L. & Amiji, M. CNS delivery of targeted protein degraders. J. Control. Release 372, 661–673 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wager, T. T., Hou, X., Verhoest, P. R. & Villalobos, A. Central nervous system multiparameter optimization desirability: application in drug discovery. ACS Chem. Neurosci. 7, 767–775 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • La, D. et al. Anaplastic lymphoma kinase (ALK) degraders and uses thereof. US patent WO/2026/035999 (2026).

  • Drilon, A. et al. ROS1-dependent cancers—biology, diagnostics and therapeutics. Nat. Rev. Clin. Oncol. 18, 35–55 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Camidge, D. R. Lorlatinib should not be considered as the preferred first-line option in patients with advanced ALK rearranged NSCLC. J. Thorac. Oncol. 16, 528–531 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, D. et al. Characterization of on-target adverse events caused by TRK inhibitor therapy. Ann. Oncol. 31, 1207–1215 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Matyskiela, M. E. et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature 535, 252–257 (2016).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Nishiguchi, G. et al. Selective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines. Nat. Commun. 15, 482 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sakamoto, H. et al. CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell 19, 679–690 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Watson, E. R. et al. Molecular glue CELMoD compounds are regulators of cereblon conformation. Science 378, 549–553 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Petzold, G., Fischer, E. S. & Thoma, N. H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase. Nature 532, 127–130 (2016).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Petzold, G. et al. Mining the CRBN target space redefines rules for molecular glue-induced neosubstrate recognition. Science 389, eadt6736 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Krissinel, E. & Henrick, K. Inference of macromolecular assemblies from crystalline state. J. Mol. Biol. 372, 774–797 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shiba-Ishii, A. et al. Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer. Nat. Cancer 3, 710–722 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Highlights of Prescribing Information for Lorbrena https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210868s004lbl.pdf (2021).

  • Zou, H. Y. et al. PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell 28, 70–81 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Taipale, M. et al. Chaperones as thermodynamic sensors of drug-target interactions reveal kinase inhibitor specificities in living cells. Nat. Biotechnol. 31, 630–637 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pacheco, J. M. et al. Natural history and factors associated with overall survival in stage IV ALK-rearranged non-small cell lung cancer. J. Thorac. Oncol. 14, 691–700 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lin, J. J. et al. NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK-mutant oncoproteins, including lorlatinib-resistant compound mutations. Cancer Discov. 14, 2367–2386 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Poirson, J. et al. Proteome-scale discovery of protein degradation and stabilization effectors. Nature 628, 878–886 (2024).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Reichermeier, K. M. et al. PIKES analysis reveals response to degraders and key regulatory mechanisms of the CRL4 network. Mol. Cell 77, 1092–1106 e1099 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Orthofer, M. et al. Identification of ALK in thinness. Cell 181, 1246–1262 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Matyskiela, M. E. et al. SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate. Nat. Chem. Biol. 14, 981–987 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lin, J. J. et al. ALKOVE-1: efficacy and safety of neladalkib in patients with advanced ALK+ NSCLC. J. Clin. Oncol. 44, 8503–8503 (2026).

    Article 

    Google Scholar
     

  • Dagogo-Jack, I. et al. MET alterations are a recurring and actionable resistance mechanism in ALK-positive lung cancer. Clin. Cancer Res. 26, 2535–2545 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eide, C. A. et al. Overcoming clinical BCR-ABL1 compound mutant resistance with combined ponatinib and asciminib therapy. Cancer Cell 42, 1486–1488 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nagasaka, M. et al. The novel ALK K1150dup mutation mediates resistance to frontline lorlatinib and retains sensitivity to gilteritinib. NPJ Precis. Oncol. https://doi.org/10.1038/s41698-026-01477-z (2026).

  • Bird, S. & Pawlyn, C. IMiD resistance in multiple myeloma: current understanding of the underpinning biology and clinical impact. Blood 142, 131–140 (2023).

    CAS 
    PubMed 

    Google Scholar
     

  • Isozaki, H. et al. Therapy-induced APOBEC3A drives evolution of persistent cancer cells. Nature 620, 393–401 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Katayama, R. et al. Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. Clin. Cancer Res. 20, 5686–5696 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de la Rosa-Trevin, J. M. et al. Scipion: A software framework toward integration, reproducibility and validation in 3D electron microscopy. J. Struct. Biol. 195, 93–99 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Scheres, S. H. RELION: implementation of a Bayesian approach to cryo-EM structure determination. J. Struct. Biol. 180, 519–530 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meng, E. C. et al. UCSF ChimeraX: tools for structure building and analysis. Protein Sci. 32, e4792 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Croll, T. I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D 74, 519–530 (2018).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yamashita, K., Palmer, C. M., Burnley, T. & Murshudov, G. N. Cryo-EM single-particle structure refinement and map calculation using Servalcat. Acta Crystallogr. D 77, 1282–1291 (2021).

    Article 
    ADS 
    CAS 

    Google Scholar
     

  • Dallakyan, S. & Olson, A. J. Small-molecule library screening by docking with PyRx. Methods Mol. Biol. 1263, 243–250 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • MacLean, B. et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics https://doi.org/10.1093/bioinformatics/btq054 (2010).

  • Yamazaki, S. et al. Translational pharmacokinetic-pharmacodynamic modeling for an orally available novel inhibitor of anaplastic lymphoma kinase and c-Ros oncogene 1. J. Pharmacol. Exp. Ther. 351, 67–76 (2014).

    Article 
    PubMed 

    Google Scholar
     



  • Source link

    Keep Up to Date with the Most Important News

    By pressing the Subscribe button, you confirm that you have read and are agreeing to our Privacy Policy and Terms of Use
    Add a comment Add a comment

    Leave a Reply

    Your email address will not be published. Required fields are marked *

    Previous Post
    Imaging cellular activity across all organs reveals body-wide circuits

    Imaging cellular activity across all organs reveals body-wide circuits

    Next Post
    Anodic Pd membrane H2 extraction enhances thermochemical dehydrogenation

    Anodic Pd membrane H2 extraction enhances thermochemical dehydrogenation

    Advertisement