Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282.
Autor: | Verma MK; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115. Electronic address: mahipverma@lupin.com., Samant C; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Kale R; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Patra S; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Mahajan N; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Gholve MK; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Marisetti A; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Sunkara B; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Naik A; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Shingare M; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Reddy M; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Bokare AM; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Akarte A; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Koul S; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Nigade PB; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Patil VB; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Modi D; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Ahirrao P; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Pawar S; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Kuldharan S; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Dinchhana L; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Mehta M; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Gundu J; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Jana N; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Vidhate P; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Mahangare SJ; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Shukla MR; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Goel RN; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Bhonde M; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Kamboj RK; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115., Palle VP; Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115. |
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Jazyk: | angličtina |
Zdroj: | Biochemical and biophysical research communications [Biochem Biophys Res Commun] 2022 Dec 31; Vol. 637, pp. 267-275. Date of Electronic Publication: 2022 Nov 15. |
DOI: | 10.1016/j.bbrc.2022.11.038 |
Abstrakt: | Phosphoinositide 3-kinase (PI3K) pathway mediates key signaling events downstream to B-cell receptor (BCR) for survival of mature B-cells, and overexpression or overactivation of PI3Kδ is crucial for B-cell malignancies such as diffuse large B-cell lymphoma (DLBCL). Small molecule PI3Kδγ inhibitors, with a known potential to reduce activated B-cell (ABC)-DLBCL transformation, form an important class of therapeutics approved for follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL). In this study, we describe discovery of a potent, selective and efficacious dual PI3Kδγ inhibitor, LL-00084282, having a differentiated efficacy profile in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines. LL-00084282 displayed high potency and superior PI3Kδγ engagement with excellent selectivity over other PI3K isoforms at both IC Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Manojkumar Ramprasad SHUKLA has patent #WO2016001855A1 issued to LUPIN LIMITED. (Copyright © 2022 Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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