SRX3305

**SRX3305** is a potent small-molecule triple inhibitor targeting **BTK**, **PI3K** (particularly isoforms α and δ), and **BRD4** (both BD1 and BD2 bromodomains), with IC50 values of 6.5 nM for BTK, 15 nM for PI3Kα, 4 nM for PI3Kδ, 77 nM for BRD4 BD1, and 95 nM for BRD4 BD2. It demonstrates enhanced potency against the drug-resistant BTK C481S mutant (IC50 9 nM) compared to predecessors like SRX3262, irreversibly binding BTK to disrupt B-cell receptor signaling while simultaneously inhibiting PI3K/AKT/mTOR and BRD4/MYC pathways. Preclinical studies show strong cytotoxicity in mantle cell lymphoma (MCL) cell lines (e.g., IC50 58 nM in JeKo-1, 1 nM in Mino) and chronic lymphocytic leukemia (CLL) models, including ibrutinib-resistant cells, by inducing cell cycle arrest (S/G2 phase), apoptosis, reduced MYC expression, and blocked migration toward chemokines like CXCL-12/13; it spares healthy PBMCs and stromal cells.[1][2][3][5]