Preclinical evidence for the effective use of TL-895, a highly selective and potent second-generation BTK inhibitor, for the treatment of B-cell malignancies

• Published in: Scientific reports Vol. 13; no. 1; p. 20412
• Main Authors: Goodstal, Samantha M, Lin, Jing, Crandall, Timothy, Crowley, Lindsey, Bender, Andrew T, Pereira, Albertina, Soloviev, Maria, Wesolowski, John S, Iadevaia, Riham, Schelhorn, Sven-Eric, Ross, Edith, Morandi, Federica, Ma, Jianguo, Clark, Anderson
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 21.11.2023; Nature Portfolio
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Antibody-dependent cell-mediated cytotoxicity; ATP; B-cell lymphoma; B-Lymphocytes - metabolism; Bruton's tyrosine kinase; Burkitt's lymphoma; Cell culture; Cell viability; Chromium; Chronic lymphocytic leukemia; Cytotoxicity; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - pathology; Malignancy; Phosphorylation; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Tumor cell lines; Tumors; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-023-47735-z

TL-895 (formerly known as M7583) is a potent, highly selective, adenosine triphosphate (ATP)-competitive, second-generation, irreversible inhibitor of Bruton's tyrosine kinase (BTK). We characterized its biochemical and cellular effects in in vitro and in vivo models. TL-895 was evaluated preclinically for potency against BTK using IC concentration-response curves; selectivity using a 270-kinase panel; BTK phosphorylation in Ramos Burkitt's lymphoma cells by ProteinSimple Wes analysis of one study; anti-proliferative effects in primary chronic lymphocytic leukemia (CLL) blasts; cell viability effects in diffuse large B-cell lymphoma (DLBCL) and mantle-cell lymphoma (MCL) cell lines; effects on antibody-dependent cell-mediated cytotoxicity (ADCC) from Daudi cells and chromium-51 release from human tumor cell lines; and efficacy in vivo using four MCL xenograft model and 21 DLBCL patient-derived xenograft (PDX) models (subtypes: 9 ABC, 11 GCB, 1 Unclassified). TL-895 was active against recombinant BTK (average IC 1.5 nM) and inhibited only three additional kinases with IC within tenfold of BTK activity. TL-895 inhibited BTK auto-phosphorylation at the Y223 phosphorylation site (IC 1-10 nM). TL-895 inhibited the proliferation of primary CLL blasts in vitro and inhibited growth in a subset of activated DLBCL and MCL cell lines. TL-895 inhibited the ADCC mechanism of therapeutic antibodies only at supra-clinical exposure levels. TL-895 significantly inhibited tumor growth in the Mino MCL xenograft model and in 5/21 DLBCL PDX models relative to vehicle controls. These findings demonstrate the potency of TL-895 for BTK and its efficacy in models of B-cell lymphoma despite its refined selectivity.