Cixutumumab

Targeting bromodomain and extra-terminal (BET) proteins is a promising therapeutic strategy for acute myeloid leukemia (AML). However, clinical development of conventional BET inhibitors has been limited by dose-related toxicities and compensatory resistance. Proteolysis-targeting chimeras (PROTACs) offer a catalytic and often more selective alternative by degrading target proteins via the ubiquitin-proteasome system. In this work, we designed and synthesized a series of novel BET PROTACs based on the clinical inhibitor ABBV-075. Through systematic optimization of linker length/composition and E3 ligase ligands (CRBN or VHL), we identified two highly potent PROTACs, A10 (CRBN-based) and A12 (VHL-based). Both compounds effectively degraded BET proteins, inhibited cell proliferation, induced cell-cycle arrest, and promoted apoptosis in MV4-11 AML cells. In MV4-11 xenograft models, A10 (6 mg/kg) and A12 (2 mg/kg) demonstrated significant tumor growth inhibition (76.2% and 60.5%, respectively). A comprehensive drug-likeness assessment revealed that while A12 exhibited higher systemic exposure in pharmacokinetic studies, A10 displayed a markedly superior safety profile with minimal hepatorenal toxicity. The favorable efficacy-safety balance of A10 underscores its strong potential as a preclinical candidate for AML therapy. This study highlights how rational PROTAC optimization can yield degraders with enhanced therapeutic windows, providing a promising path forward for targeted protein degradation in AML.

Ataxia telangiectasia and Rad3-related kinase (ATR) is a pivotal DNA damage response regulator. While several ATR inhibitors have entered clinical trials, none have yet been approved for therapeutic use. A potent ATR degrader A12 based on the pyrrolo[3,4-d]pyrimidine scaffold was designed and synthesized, with the ability not only to induce proteasomal degradation of ATR (DC₅₀: 127 nM, D_max: 72%) but also of CHK1 (DC₅₀: 135 nM, D_max: 70%) in several colorectal cancer cells. It exhibits strong antiproliferative activity (IC₅₀: 55 nM) and rapidly triggers apoptosis. In LoVo xenograft mouse model, A12 monotherapy (30 mg/kg) achieved outstanding tumor growth inhibition (TGI: 74%) without apparent toxicity. Combination with A12 (10 mg/kg) and cetuximab (3 mg/kg) further enhanced efficacy (TGI: 81%) with a favorable safety profile. These findings highlight that ATR degraders such as A12, which also degrade CHK1 simultaneously, represents as a promising therapeutic strategy for colorectal cancer and potentially other tumor types.