TGRX-3247

**TGRX-3247** is a novel, super-potent, orally active heterobifunctional degrader independently developed by TargetRx (Shenzhen TargetRx) as a targeted protein degrader for **chronic myeloid leukemia (CML)**. It recruits the BCR::ABL1 oncoprotein fusion to the **E3 ligase cereblon (CRBN)**, inducing ubiquitination and proteasomal degradation, thereby eliminating both kinase-dependent and kinase-independent functions of BCR::ABL1. This addresses resistance to approved tyrosine kinase inhibitors (TKIs) by potently targeting a broad spectrum of **orthosteric mutations (e.g., T315I, T315M)**, **allosteric mutations (e.g., A337V, P465S, V468F, I502L)**, and **compound mutations (e.g., E255V/T315I, F359V/T315I, Y253H/T315I)**, with picomolar IC50 values (<0.06 nM in sensitive CML lines, <1 nM in resistant mutants) and high selectivity (IC50 >10 μM in normal cells). Preclinical data show sustained degradation post-washout, robust anti-proliferation, and dose-dependent tumor growth inhibition in CML xenograft models (e.g., 99.8% TGI at 3 mpk in K562, 82% TGI at 10 mpk BID in T315I). It holds potential for deeper molecular responses and higher treatment-free remission rates in CML.[1][3][11]