KAT/3BP: A Metabolism-Targeting Agent with Single and Combination Activity in Aggressive B-Cell Lymphomas.

Background/objectives: Reprogramming of the cellular metabolism is a hallmark of cancer, offering therapeutic opportunities to target cancer cell vulnerabilities for therapeutic purposes. 3-Bromopyruvate (3BP) is a small alkylating agent that functions as an anti-metabolite, targeting key substrates in cancer metabolism and demonstrating antitumor activity across multiple cancer types. However, unformulated 3BP is associated with significant toxicity.

Novel PI3kδ inhibitor roginolisib synergizes with venetoclax in hematologic malignancies.

The phosphoinositide 3-kinase (PI3K) pathway remains a potent drug target in hematological malignancies despite the challenges that have affected clinical drug development, particularly unpredictable toxicity, and inherent/acquired drug resistance. Herein, we tested the activity of a novel PI3Kδ selective, non-ATP competitive inhibitor, roginolisib (IOA-244), in hematological malignancies including diffuse large B cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). To identify rational actionable combination partners that can be tested in hematologic malignancies, an unbiased pharmacological screening of 474 compounds was carried out in two lymphoma cell lines.

Targeting of PIM Kinases Shows Single Agent Efficacy and Synergizes With BCL2 Inhibitors in Diffuse Large B Cell Lymphoma of the ABC Subtype.

The PIM family of serine/threonine kinases (PIM1, PIM2, and PIM3) are involved in the development of cancer and represent promising therapeutic targets. We investigated the therapeutic potential of targeting PIM kinases in diffuse large B-cell lymphoma (DLBCL), particularly the activated B-cell-like (ABC) subtype, using the pan-PIM inhibitor AZD1208. We demonstrated that PIM1 and PIM2 are more highly expressed in ABC- cells than in germinal center B-cell-like (GCB) -DLBCL cells, and that ABC-DLBCL cell lines are more sensitive to PIM inhibition with AZD1208.

IOA-244 is a Non-ATP-competitive, Highly Selective, Tolerable PI3K Delta Inhibitor That Targets Solid Tumors and Breaks Immune Tolerance.

Unlabelled: PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ inhibition in solid tumors has recently emerged as a potential novel anticancer therapy through the modulation of T-cell responses and direct antitumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non-ATP-competitive PI3Kδ inhibitor, for the treatment of solid tumors.

Study of the antilymphoma activity of pracinostat reveals different sensitivities of DLBCL cells to HDAC inhibitors.

Histone deacetylase inhibitors (HDACis) are antitumor agents with distinct efficacy in hematologic tumors. Pracinostat is a pan-HDACi with promising early clinical activity. However, similar to other HDACis, its activity as a single agent is limited.