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  2. Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282

Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and preclinical characterization of LL-00084282

  • Biochem Biophys Res Commun. 2022 Dec 31:637:267-275. doi: 10.1016/j.bbrc.2022.11.038.
Mahip K Verma 1 Charudatt Samant 2 Ramesh Kale 2 Sukanya Patra 2 Nilesh Mahajan 2 Milind K Gholve 2 Ajitkumar Marisetti 2 Brahmam Sunkara 2 Aditya Naik 2 Manisha Shingare 2 Madhusudhan Reddy 2 Anand M Bokare 2 Atul Akarte 2 Sarita Koul 2 Prashant B Nigade 2 Vinod B Patil 2 Dipak Modi 2 Prajakta Ahirrao 2 Shashikant Pawar 2 Sandip Kuldharan 2 Lal Dinchhana 2 Maneesh Mehta 2 Jayasagar Gundu 2 Nirmal Jana 2 Prashant Vidhate 2 Sachin Jaysing Mahangare 2 Manojkumar R Shukla 2 Rajan N Goel 2 Mandar Bhonde 2 Rajender Kumar Kamboj 2 Venkata P Palle 2
Affiliations

Affiliations

  • 1 Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115. Electronic address: [email protected].
  • 2 Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115.
Abstract

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 IC50/90 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.

Keywords

Basophil activation; Diffuse large B-cell lymphoma; Indolent non-Hodgkin's lymphoma; Phosphoinositide 3-kinase; Tumor growth inhibition; Xenograft.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15245
    99.88%, PI3Kβ Inhibitor