Sone-026 <TESTED>

| Isoform | IC₅₀ (nM) | Selectivity (vs PI3Kα) | |---------|-----------|------------------------| | PI3Kδ | 0.8 ± 0.1 | 250‑fold | | PI3Kγ | 1.2 ± 0.2 | 210‑fold | | PI3Kα | > 200 | — | | PI3Kβ | > 180 | — |

Enzyme assays were performed using recombinant human PI3K catalytic subunits (Eurofins DiscoverX) with a radiometric ADP‑Glo™ read‑out. SONE‑026 displayed reversible, ATP‑competitive inhibition confirmed by kinetic analysis (K_i ≈ 0.5 nM).

Mara sat on a stone slab, the hydrophone still recording, and began to ask questions. The conversation unfolded like a duet:

Mara understood. The lighthouse could become a beacon not just for ships but for the planet’s wellbeing. She could relay the emulator’s data to research stations worldwide, turning the lighthouse into a global warning system.

She pulled out her notebook, jotting down the coordinates of the emulator and the data streams it was already broadcasting. The lighthouse’s flashing light, once a simple guide for sailors, now pulsed in a Morse‑like rhythm: SOS for the planet.

The class I phosphoinositide‑3‑kinases (PI3Ks) are heterodimeric enzymes that phosphorylate phosphatidyl‑inositol‑4,5‑bisphosphate (PIP₂) to generate the second messenger phosphatidyl‑inositol‑3,4,5‑trisphosphate (PIP₃). Among the four catalytic isoforms (α, β, δ, γ), PI3Kδ and PI3Kγ are predominantly expressed in leukocytes and regulate B‑cell receptor (BCR) signaling, cytokine production, and chemotaxis. Aberrant activation of these isoforms sustains survival of chronic lymphocytic leukemia (CLL), mantle‑cell lymphoma (MCL), and contributes to the inflammatory cascade in autoimmune diseases such as ulcerative colitis (UC) and rheumatoid arthritis (RA) (Miller et al., 2021; Zhou & He, 2022). SONE-026

Approved PI3Kδ inhibitors (idelalisib, duvelisib, umbralisib) have demonstrated efficacy but are limited by on‑target toxicities (immune‑mediated colitis, hepatotoxicity) and the emergence of resistance mutations in the PI3Kδ kinase domain (Wang et al., 2023). Simultaneous inhibition of PI3Kγ, which modulates myeloid cell migration and the tumor micro‑environment, is hypothesized to enhance anti‑tumor immunity and dampen inflammatory responses (Gao et al., 2020).

SONE‑026 (development code: SONE‑026; generic name: piqorimib) was discovered by Sone Pharmaceuticals in 2019 through a focused library of quinazoline scaffolds targeting the PI3Kδ/γ ATP‑binding pocket. The compound entered IND‑enabling studies in 2021 and has since progressed through pre‑clinical validation and early‑phase clinical trials in both oncology and gastroenterology.

This review collates all publicly available data on SONE‑026 up to March 2026, critically evaluates its pharmacological profile, and outlines the ongoing clinical development program.

| Species | Route | C_max (µM) | T_max (h) | t½ (h) | Oral F (%) | AUC₀‑∞ (µM·h) | |---------|-------|------------|-----------|--------|------------|---------------| | Rat | PO | 1.2 | 1.1 | 9.2 | 42 | 12.3 | | Dog | PO | 0.9 | 1.3 | 8.8 | 48 | 10.5 | | Human | PO | 0.65 (75 mg) | 1.0 | 9.5 | 45 (fasted) | 8.4 |

Food increased exposure by ~ 30 % (high‑fat meal). No significant accumulation after qd dosing for 14 days (steady‑state achieved by day 5). | Isoform | IC₅₀ (nM) | Selectivity (vs

| Parameter | Value / Observation | |-----------|----------------------| | Chemical class | 4‑(3‑chloro‑4‑fluorophenyl)‑6‑(4‑pyridyl)‑7‑[1‑(2‑methoxy‑ethyl)piperidin‑4‑yl]quinazoline | | Molecular weight | 465 Da | | cLogP | 2.9 | | pKa (basic nitrogen) | 7.8 | | Key SAR features | • Hinge‑binding quinazoline core (N1‑H forms H‑bond to Val828 in PI3Kδ)
• 4‑chloro‑fluoro phenyl substituent enhances PI3Kδ selectivity
• Piperidine side‑chain confers PI3Kγ potency and improves solubility | | Synthetic route | 6‑step convergent synthesis from 2‑amino‑4‑fluorobenzonitrile; final N‑alkylation with (2‑methoxy‑ethyl)‑piperidine (overall yield ≈ 38 %) | | Patent | WO2022/147893 (granted 2023) – claims quinazoline derivatives with dual PI3Kδ/γ activity and methods of use in B‑cell malignancies and inflammatory diseases |

The lead optimization campaign (2019‑2021) focused on achieving > 150‑fold selectivity for PI3Kδ/γ over PI3Kα/β while maintaining oral bioavailability. Substituent scanning at the 6‑position of the quinazoline core identified the 4‑pyridyl moiety as a critical determinant of PI3Kγ affinity (IC₅₀ = 1.2 nM). Introduction of a fluorine atom at the para‑position of the phenyl ring reduced CYP3A4 metabolism, resulting in a ~ 2‑fold increase in in‑vivo exposure in rodents.

Background: Dysregulated phosphoinositide‑3‑kinase (PI3K) signaling, particularly through the δ and γ isoforms, drives the proliferation and survival of malignant B‑cells and fuels pathogenic immune activation in autoimmune diseases. Existing PI3K inhibitors are limited by isoform‑selectivity, off‑target toxicities, and modest efficacy.

Objective: To review the discovery, pre‑clinical pharmacology, early‑phase clinical development, and therapeutic potential of SONE‑026, a novel oral small‑molecule that potently and simultaneously inhibits PI3Kδ (IC₅₀ = 0.8 nM) and PI3Kγ (IC₅₀ = 1.2 nM) while sparing PI3Kα/β.

Methods: A systematic literature search (PubMed, Embase, clinicaltrials.gov) was performed for all peer‑reviewed articles, conference abstracts, and regulatory filings concerning SONE‑026 up to March 2026. Data were extracted on (i) medicinal chemistry and structure‑activity relationships, (ii) in‑vitro and in‑vivo pharmacodynamics, (iii) pharmacokinetics (PK) and drug‑drug interaction (DDI) profile, (iv) safety and tolerability, and (v) efficacy outcomes from phase I/II trials in chronic lymphocytic leukemia (CLL), mantle‑cell lymphoma (MCL), and moderate‑to‑severe ulcerative colitis (UC). Mara understood

Results: SONE‑026 is a quinazoline‑based ATP‑competitive inhibitor that binds the conserved “hinge” region of the PI3Kδ/γ catalytic domains, achieving > 200‑fold selectivity over PI3Kα/β. In murine xenograft models of CLL and MCL, oral administration (10–30 mg kg⁻¹ qd) produced > 90 % tumor growth inhibition (TGI) and induced durable apoptosis (cleaved‑caspase‑3 ↑ 3‑fold). Pharmacokinetic studies in rats and dogs demonstrated rapid absorption (T_max ≈ 1 h), moderate bioavailability (≈ 45 %), a half‑life of 8–10 h, and minimal CYP3A4 induction.

Phase I dose‑escalation (N = 48) in relapsed/refractory B‑cell malignancies identified 75 mg qd as the recommended phase II dose (RP2D) based on pharmacodynamic (pAKT↓ > 80 %) and safety data (no grade ≥ 3 infections, neutropenia ≤ 20 %). Preliminary efficacy (overall response rate, ORR = 48 %; complete response, CR = 12 %) compared favorably with idelalisib (ORR ≈ 45 %).

In a parallel phase Ib/IIa trial in moderate‑to‑severe UC (N = 62), SONE‑026 50 mg qd achieved clinical remission at week 8 in 38 % of patients versus 15 % with placebo (p = 0.004). Endoscopic improvement correlated with reduced mucosal pAKT and IL‑17A levels. The safety profile was acceptable; the most common adverse events were transient diarrhea (23 %) and mild transaminase elevations (≤ 2 × ULN).

Conclusion: SONE‑026 emerges as a highly selective dual PI3Kδ/γ inhibitor with a robust pre‑clinical rationale, favorable pharmacokinetics, and promising early‑clinical efficacy in both hematologic malignancies and inflammatory bowel disease. Ongoing phase II/III studies will define its therapeutic niche and comparative advantage over existing PI3K‑targeted agents.

Keywords: SONE‑026, PI3Kδ, PI3Kγ, dual inhibition, B‑cell lymphoma, ulcerative colitis, targeted therapy