PI3K‑δ inhibition; IBW‑959z; targeted therapy; B‑cell lymphoma; small‑molecule inhibitor; pre‑clinical development 1. Introduction The phosphoinositide 3‑kinase (PI3K) signalling axis regulates cell growth, survival, and metabolism. Dysregulation of the PI3K pathway is a hallmark of many cancers, with the PI3K‑δ isoform being especially critical in B‑cell development and function (1,2). Clinically approved PI3K‑δ inhibitors (e.g., idelalisib, duvelisib) have demonstrated efficacy in chronic lymphocytic leukaemia (CLL) and follicular lymphoma, yet their therapeutic windows are limited by off‑target toxicities, notably hepatotoxicity and colitis (3,4).
IBW‑959z: A Novel Small‑Molecule Inhibitor of the PI3K‑δ Pathway with Potent Antitumor Activity in Pre‑clinical Models IBW-959z
To overcome these limitations, we pursued a structure‑based design strategy targeting a unique hydrophobic pocket adjacent to the ATP‑binding site of PI3K‑δ. The resulting compound, IBZ‑959z (chemical name: ‑(4‑(4‑fluorophenyl)‑2‑pyrimidinyl)-2‑(3‑pyridyl)‑1‑pyrrolidine‑carboxamide), exhibits a novel heterocyclic core that confers high potency and isoform selectivity. Clinically approved PI3K‑δ inhibitors (e
¹ Department of Medicinal Chemistry, University of Cambridge, UK ² Institute of Molecular Pharmacology, Shanghai Jiao Tong University, China ³ Cancer Biology Program, Universidad Nacional Autónoma de México, Mexico ⁴ Department of Pharmacology, Seoul National University, South Korea ⁵ Department of Oncology, Johns Hopkins University School of Medicine, USA ¹ Department of Medicinal Chemistry
| Cell line | GI₅₀ (nM) | % Inhibition of p‑AKT (Ser473) at 1 nM | |-----------|----------|----------------------------------------| | OCI‑Ly3 | 0.12 ± 0.02 | 95 % | | MEC‑1 | 0.18 ± 0.03 | 92 % | | A549 | 31 ± 4 | 18 % | | MCF‑7 | 38 ± 5 | 22 % |
PI3K‑δ inhibition; IBW‑959z; targeted therapy; B‑cell lymphoma; small‑molecule inhibitor; pre‑clinical development 1. Introduction The phosphoinositide 3‑kinase (PI3K) signalling axis regulates cell growth, survival, and metabolism. Dysregulation of the PI3K pathway is a hallmark of many cancers, with the PI3K‑δ isoform being especially critical in B‑cell development and function (1,2). Clinically approved PI3K‑δ inhibitors (e.g., idelalisib, duvelisib) have demonstrated efficacy in chronic lymphocytic leukaemia (CLL) and follicular lymphoma, yet their therapeutic windows are limited by off‑target toxicities, notably hepatotoxicity and colitis (3,4).
IBW‑959z: A Novel Small‑Molecule Inhibitor of the PI3K‑δ Pathway with Potent Antitumor Activity in Pre‑clinical Models
To overcome these limitations, we pursued a structure‑based design strategy targeting a unique hydrophobic pocket adjacent to the ATP‑binding site of PI3K‑δ. The resulting compound, IBZ‑959z (chemical name: ‑(4‑(4‑fluorophenyl)‑2‑pyrimidinyl)-2‑(3‑pyridyl)‑1‑pyrrolidine‑carboxamide), exhibits a novel heterocyclic core that confers high potency and isoform selectivity.
¹ Department of Medicinal Chemistry, University of Cambridge, UK ² Institute of Molecular Pharmacology, Shanghai Jiao Tong University, China ³ Cancer Biology Program, Universidad Nacional Autónoma de México, Mexico ⁴ Department of Pharmacology, Seoul National University, South Korea ⁵ Department of Oncology, Johns Hopkins University School of Medicine, USA
| Cell line | GI₅₀ (nM) | % Inhibition of p‑AKT (Ser473) at 1 nM | |-----------|----------|----------------------------------------| | OCI‑Ly3 | 0.12 ± 0.02 | 95 % | | MEC‑1 | 0.18 ± 0.03 | 92 % | | A549 | 31 ± 4 | 18 % | | MCF‑7 | 38 ± 5 | 22 % |