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.
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 50/90 concentrations in biochemical and cell-based assays. In contrast to selective PI3Kδ inhibitors, LL-00084282 showed superior and potent anticancer activity in both ABC- and GCB-DLBCL cell lines. LL-00084282 demonstrated in-vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability. Furthermore, LL-00084282 inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, showing potential implications in immunoinflammatory conditions. Good pharmacokinetic properties in higher species and desirable efficacy profile highlights potential of this novel PI3Kδγ inhibitor for further clinical evaluation in DLBCL patients.
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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