FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4200171855> ?p ?o ?g. }

• W4200171855 abstract "Oncogenic ROS1 and ALK rearrangements are detected in up to 3% and up to 5% of advanced non-small cell lung cancer (NSCLC), respectively, with up to 40% of patients presenting with brain metastases at diagnosis. Although there are FDA-approved ROS1 and ALK inhibitors, there is a need for next-generation brain-penetrant inhibitors that have activity against drug-resistance mutations while sparing tropomyosin kinase B (TRKB) function in the central nervous system (CNS). TRKB inhibition in the CNS has been implicated in adverse events such as cognitive impairment, mood disorders, sleep effects or sleep disturbances, dizziness, ataxia or gait/motor disturbances, and weight gain, which have been observed with FDA-approved dual TRK/ROS1 inhibitor entrectinib and FDA-approved ALK inhibitor lorlatinib. TRKB-related CNS adverse events present a key challenge for the development of next-generation ROS1 and ALK therapies. We previously reported the discovery of NVL-520 and NVL-655, preclinical inhibitors of ROS1 and ALK, respectively, which have demonstrated activity against common drug-resistance mutations, selectivity versus TRKB, and brain penetrance in preclinical experiments. An important part of the discovery process was generating reliable and relevant TRKB potency measurements to enable structure-activity relationship (SAR) efforts. Here we describe four in vitro TRKB potency assays and explain their utility in guiding selectivity optimization for new inhibitors. These assays include (1) biochemical, (2) cell viability, (3) cellular coupled-enzyme, and (4) direct cellular phosphorylation readouts. Although biological contexts vary, each assay exhibits good cross-correlations, and we recommend multi-assay testing to improve confidence in evaluating TRKB inhibition. Using these assays, we present a multi-assay analysis of the preclinical TRKB potency and selectivity of NVL-520 and NVL-655 alongside FDA-approved or experimental inhibitors of ROS1 (crizotinib, entrectinib, repotrectinib, and taletrectinib) and ALK (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and ensartinib). In these preclinical assays, we observed entrectinib and lorlatinib to exhibit poor ROS1-vs-TRKB and ALK G1202R-vs-TRKB selectivity, respectively, which we believe is consistent with their CNS adverse events. In the same experiment, we observed NVL-520 and NVL-655 to exhibit selectivity across all assays, including for ROS1 G2032R and ALK G1202R/L1196M mutations, respectively. In conclusion, we have devised a multi-assay approach to evaluate TRKB inhibition and guide discovery of selective ROS1 and ALK inhibitors, with the goal of minimizing adverse events and driving durable responses for patients.Citation Format: Anupong Tangpeerachaikul, Joshua C. Horan, Henry E. Pelish. Evaluating TRKB activity of novel preclinical brain-penetrant ROS1 and ALK inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P247." @default.
• W4200171855 created "2021-12-31" @default.
• W4200171855 creator A5022400371 @default.
• W4200171855 creator A5033526813 @default.
• W4200171855 creator A5074480973 @default.
• W4200171855 date "2021-12-01" @default.
• W4200171855 modified "2023-10-16" @default.
• W4200171855 title "Abstract P247: Evaluating TRKB activity of novel preclinical brain-penetrant ROS1 and ALK inhibitors" @default.
• W4200171855 doi "https://doi.org/10.1158/1535-7163.targ-21-p247" @default.
• W4200171855 hasPublicationYear "2021" @default.
• W4200171855 type Work @default.
• W4200171855 citedByCount "0" @default.
• W4200171855 crossrefType "proceedings-article" @default.
• W4200171855 hasAuthorship W4200171855A5022400371 @default.
• W4200171855 hasAuthorship W4200171855A5033526813 @default.
• W4200171855 hasAuthorship W4200171855A5074480973 @default.
• W4200171855 hasConcept C121608353 @default.
• W4200171855 hasConcept C126322002 @default.
• W4200171855 hasConcept C134139212 @default.
• W4200171855 hasConcept C160539049 @default.
• W4200171855 hasConcept C170493617 @default.
• W4200171855 hasConcept C2775999482 @default.
• W4200171855 hasConcept C2776232967 @default.
• W4200171855 hasConcept C2776256026 @default.
• W4200171855 hasConcept C2778347629 @default.
• W4200171855 hasConcept C2779422266 @default.
• W4200171855 hasConcept C2781182431 @default.
• W4200171855 hasConcept C502942594 @default.
• W4200171855 hasConcept C60644358 @default.
• W4200171855 hasConcept C71924100 @default.
• W4200171855 hasConcept C74187038 @default.
• W4200171855 hasConcept C86803240 @default.
• W4200171855 hasConcept C92020748 @default.
• W4200171855 hasConcept C97124661 @default.
• W4200171855 hasConcept C98274493 @default.
• W4200171855 hasConceptScore W4200171855C121608353 @default.
• W4200171855 hasConceptScore W4200171855C126322002 @default.
• W4200171855 hasConceptScore W4200171855C134139212 @default.
• W4200171855 hasConceptScore W4200171855C160539049 @default.
• W4200171855 hasConceptScore W4200171855C170493617 @default.
• W4200171855 hasConceptScore W4200171855C2775999482 @default.
• W4200171855 hasConceptScore W4200171855C2776232967 @default.
• W4200171855 hasConceptScore W4200171855C2776256026 @default.
• W4200171855 hasConceptScore W4200171855C2778347629 @default.
• W4200171855 hasConceptScore W4200171855C2779422266 @default.
• W4200171855 hasConceptScore W4200171855C2781182431 @default.
• W4200171855 hasConceptScore W4200171855C502942594 @default.
• W4200171855 hasConceptScore W4200171855C60644358 @default.
• W4200171855 hasConceptScore W4200171855C71924100 @default.
• W4200171855 hasConceptScore W4200171855C74187038 @default.
• W4200171855 hasConceptScore W4200171855C86803240 @default.
• W4200171855 hasConceptScore W4200171855C92020748 @default.
• W4200171855 hasConceptScore W4200171855C97124661 @default.
• W4200171855 hasConceptScore W4200171855C98274493 @default.
• W4200171855 hasLocation W42001718551 @default.
• W4200171855 hasOpenAccess W4200171855 @default.
• W4200171855 hasPrimaryLocation W42001718551 @default.
• W4200171855 hasRelatedWork W2080538788 @default.
• W4200171855 hasRelatedWork W2292803562 @default.
• W4200171855 hasRelatedWork W2500669545 @default.
• W4200171855 hasRelatedWork W2739616532 @default.
• W4200171855 hasRelatedWork W2766826622 @default.
• W4200171855 hasRelatedWork W2885292615 @default.
• W4200171855 hasRelatedWork W2886443306 @default.
• W4200171855 hasRelatedWork W2897305758 @default.
• W4200171855 hasRelatedWork W2995958878 @default.
• W4200171855 hasRelatedWork W4200171855 @default.
• W4200171855 isParatext "false" @default.
• W4200171855 isRetracted "false" @default.
• W4200171855 workType "article" @default.