Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy

Many chemotherapies are effective against cancers that
display
high levels of genome instability by disrupting or overwhelming the
DNA damage response (DDR) to induce cell death. PARP inhibitors (PARPi)
exploit this vulnerability by stalling DNA repair, particularly in
homologous recombination-deficient cancer cells. Although PARPi are
now used to treat BRCA1/2-mutated cancers such as ovarian and breast
cancers, they are still limited to a narrow range of clinical indications
and are susceptible to acquired resistance. Here, we introduce “DNA
damage chemical inducers of proximity” (DD-CIPs), bivalent
molecules that rewire the mechanism of action of conventional PARPi.
The DD-CIPs function through chemically induced proximity between
PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate
library of DD-CIPs, we identified DD-CIP1, which induces the DDR and
apoptosis in cancer cells at two-digit nanomolar concentrations. Further
optimization yielded DD-CIP2, which induces tumor cell death at nanomolar
concentrations across diverse blood and solid cancer cells, including
cancer types that are insensitive to PARPi. Using small-cell lung
cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell
cycle arrest, and apoptosis in vitro, leading to
antitumor efficacy without substantial toxicity in preclinical SCLC
xenograft models at well-tolerated doses. Our findings demonstrate
that DD-CIPs may provide an opportunity to address the limitations
of traditional PARPi and establish chemical-induced proximity as a
strategy for modulating the DDR in cancer.

诸多化疗药物可通过破坏或过载DNA损伤应答（DNA damage response, DDR）通路诱导细胞死亡，从而对基因组不稳定性水平较高的癌症发挥治疗效果。聚腺苷二磷酸核糖聚合酶抑制剂（PARP inhibitors, PARPi）正是通过阻断DNA修复来利用这一癌症脆弱性，尤其作用于同源重组缺陷型癌细胞。尽管目前PARPi已被用于治疗BRCA1/2突变相关癌症，如卵巢癌与乳腺癌，但其临床适用范围仍较为狭窄，且易产生获得性耐药。本研究中，我们提出了“DNA损伤化学诱导邻近剂”（DNA damage chemical inducers of proximity, DD-CIPs）这一双价分子类型，其可重塑传统PARPi的作用机制。DD-CIPs通过介导PARP1/2与染色质重塑蛋白BRD4之间的化学诱导邻近作用发挥功能。从DD-CIPs候选文库中，我们筛选得到DD-CIP1，其可在两位数纳摩尔浓度下诱导癌细胞产生DDR通路激活与细胞凋亡。经过进一步优化，我们得到了DD-CIP2，其可在纳摩尔浓度下于多种血液与实体癌细胞中诱导肿瘤细胞死亡，涵盖了对PARPi不敏感的癌症类型。本研究以小细胞肺癌（small-cell lung cancer, SCLC）为模型，发现DD-CIP2可在体外触发DDR通路激活、细胞周期阻滞与细胞凋亡；在耐受剂量良好的临床前SCLC异种移植模型中，DD-CIP2展现出抗肿瘤疗效，且未引发明显毒性。本研究结果表明，DD-CIPs或可为解决传统PARPi的局限性提供新契机，并确立化学诱导邻近作为调控癌症中DDR通路的有效策略。