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Dual PI3Kδγ inhibition demonstrates potent anticancer effects in diffuse large B-cell lymphoma models: Discovery and

Mahip K Verma1, Charudatt Samant1, Ramesh Kale1

  • 1Novel Drug Discovery and Development, Lupin Limited, Lupin Research Park, Pune, Maharashtra, India, 412115.

Biochemical and Biophysical Research Communications
|November 21, 2022
PubMed

Insights

A new dual phosphoinositide 3-kinase (PI3K)δγ inhibitor, LL-00084282, shows potent anticancer activity in diffuse large B-cell lymphoma (DLBCL) models. This novel compound also demonstrates potential for treating immunoinflammatory conditions.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase (PI3K) pathway is critical for B-cell survival, with PI3Kδ overactivation implicated in B-cell malignancies like diffuse large B-cell lymphoma (DLBCL).
  • Small molecule PI3Kδγ inhibitors are approved therapeutics for certain B-cell lymphomas and leukemias, showing potential in reducing activated B-cell (ABC)-DLBCL transformation.

Purpose of the Study:

  • To discover and characterize a novel, potent, and selective dual PI3Kδγ inhibitor, LL-00084282.
  • To evaluate the efficacy of LL-00084282 in preclinical models of diffuse large B-cell lymphoma (DLBCL) and assess its potential in immunoinflammatory conditions.

Main Methods:

  • Biochemical and cell-based assays were used to determine the potency, selectivity, and engagement of LL-00084282 against PI3Kδγ and other isoforms.
  • Anticancer activity was assessed in human ABC- and germinal center B-cell (GCB)-DLBCL cell lines, and in vivo efficacy was evaluated using xenograft models.
  • Effects on pro-inflammatory cytokine secretion and basophil activation in human peripheral blood mononuclear cells (PBMCs) were investigated.

Main Results:

  • LL-00084282 demonstrated high potency and selectivity for PI3Kδγ inhibition, outperforming selective PI3Kδ inhibitors in both ABC- and GCB-DLBCL cell lines.
  • The compound exhibited significant in vivo efficacy in OCI-Ly10 and SU-DHL-6 xenografts with good tolerability.
  • LL-00084282 successfully inhibited pro-inflammatory cytokine secretion and reduced basophil activation in human PBMCs, indicating potential immunomodulatory effects.

Conclusions:

  • LL-00084282 is a potent and selective dual PI3Kδγ inhibitor with a differentiated efficacy profile in DLBCL models.
  • The compound's efficacy, good pharmacokinetic properties, and potential in immunoinflammatory conditions warrant further clinical evaluation for DLBCL treatment.
Keywords:
Basophil activationDiffuse large B-cell lymphomaIndolent non-Hodgkin's lymphomaPhosphoinositide 3-kinaseTumor growth inhibitionXenograft

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