ALK PROTAC / GNI Group - LARVOL DELTA

Discovery of an ALK degrader for lorlatinib-resistant compound mutations. (PubMed, Eur J Med Chem) - "By using WZH-15-125 as the warhead, we designed an ALK PROTAC molecule WZH-17-002 that can efficiently degrade ALK proteins with half maximal degradation concentration (DC50) values of 25 nM. Furthermore, WZH-17-002 suppresses the emergence of drug resistance and exhibits superior in vivo pharmacological efficacy than lorlatinib in ALK G1202R/L1196M xenograft mouse models. These findings suggest a potential strategy for overcoming resistance to ALK TKI therapies."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ALK

Discovery of orally bioavailable ALK PROTACs based ceritinib against ALK positive cancers. (PubMed, Eur J Med Chem) - "A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F = 14.22 %) was obtained by overall optimization of molecular properties. Furthermore, 4B significantly inhibited the growth of Karpas 299 xenografts in vivo with TGI of 49.5 % and showed superior anti-proliferative activity against G1202R mutation to Ceritinib (IC50 = 52.82 nM vs IC50 = 109.5 nM). Overall, 4B is expected to be a potential treatment for ALK-driven malignancies."

Journal • Oncology • Targeted Protein Degradation • ALK

In silico modeling of degrader-mediated ternary complex via molecular docking (ACS-Fall 2023) - "The results include conformational ensembles of the selected protein systems, and the function of a degrader along with the importance of multiple ternary conformations will be discussed. Complete results of the ALK-PROTAC-CRBN ternary complexes using the two different protein-protein docking methods and the AutoDock program will be presented."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Targeted Protein Degradation • ALK • BRD4 • CRBN

Discovery of the GSH responsive "Y-PROTACs" targeting ALK and CDK4/6 as a potential treatment for cancer. (PubMed, Eur J Med Chem) - "Herein, to achieve both tumor cell targeting and ALK degradation & CDK4/6 inhibition in one molecule, we designed and synthesized a novel GSH responsive "Y-PROTACs", Y5-3, a highly potent molecule with an IC value of 90 nM against H3122 cells, which can be cleaved into ALK PROTAC and CDK4/6 inhibitor moieties in tumor cells. Mechanism studies revealed that Y5-3 exert anti-tumor proliferation activity in vitro not only by ALK degradation and CDK4/6 inhibition, but also by ALK/CDK4 dual degradation. These properties make Y5-3 a GSH responsive multifunctional antitumor agent, and our work provide a new strategy for the development of multifunctional PROTACs."

Journal • Oncology • Targeted Protein Degradation • CDK4