LBPO.CH01 · 化学 · Late-Breaking
用于靶向抗癌治疗的DNA损伤化学邻近诱导剂（DD-CIP）
DNA damage chemical inducers of proximity (DD-CIP) for targeted cancer therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
许多癌症疗法通过压垮DNA损伤应答（DDR）通路并触发细胞死亡，优先杀伤基因组不稳定性高的肿瘤细胞。PARP抑制剂（PARPi）通过损害DNA修复来利用这一脆弱性，尤其是在同源重组（HR）缺陷的癌细胞中，如BRCA1/2突变的卵巢癌和乳腺癌。然而，PARPi的治疗范围在HR完备的癌症中往往仍受限制，并常因获得性耐药而受挫。能够重编程DDR信号以将PARP类疗法的效用扩展至更广泛癌症情境的新策略仍是一项未满足的需求。
在此，我们提出DNA损伤化学邻近诱导剂（DD-CIP），这是一类二价小分子，可强制PARP1/2与染色质调控蛋白（BRD4）之间发生邻近作用，从而重连下游DDR信号。先导DD-CIP分子能以依赖PARP1/2-BRD4相互作用的方式诱导强劲的DDR、细胞周期阻滞和凋亡性细胞死亡。进一步优化产生了DD-CIP2，其能在纳摩尔浓度下于一系列广泛的血液和实体肿瘤细胞系（包括对PARPi不敏感的癌症类型）中诱导肿瘤细胞死亡。
为进一步评估DD-CIP2的治疗潜力，我们选择小细胞肺癌（SCLC）作为代表性实体瘤模型，因为该癌症亚型尽管HR完备却表现出过度的DNA复制应激反应。因此，这为我们提供了在HR完备情境下评估DD-CIP2活性的机会。我们证明，DD-CIP2治疗在体外产生强效的抗肿瘤活性，并在异种移植研究中以良好耐受的剂量显著抑制肿瘤生长，且无明显全身毒性证据。
综上，这些发现确立了CIP作为一种重编程DDR并克服当前PARP抑制剂疗法在癌症中局限性的策略，提示其具有更广泛临床获益的潜力。
查看英文原文 English abstract
Many cancer therapies preferentially kill tumor cells with high genome instability by overwhelming DNA damage response (DDR) pathways and triggering cell death. PARP inhibitors (PARPi) exploit this vulnerability by impairing DNA repair, particularly in homologous recombination (HR)-deficient cancer cells, such as BRCA1/2-mutated ovarian and breast cancers. However, the therapeutic scope of PARPi often remains limited in HR-proficient cancers and is frequently undermined by acquired resistance. New strategies that reprogram DDR signaling to extend the utility of PARP-based therapies across broader cancer contexts are unmet need.
Here, we present DNA Damage Chemical Inducers of Proximity (DD-CIPs), the bivalent small molecules that enforces proximity between PARP1/2 and the chromatin regulator proteins (BRD4) to rewire downstream DDR signaling. Lead DD-CIP molecules can induce robust DDR, cell-cycle arrest, and apoptotic cell death in PARP1/2-BRD4 interaction dependent manner. Further optimization leads to DD-CIP2 that induces tumor cell death at nanomolar concentrations across a broad panel of hematologic and solid tumor cell lines, including cancer types that are insensitive to PARPi.
To further evaluate the therapeutic potential of DD-CIP2, we selected small-cell lung cancer (SCLC) as a representative solid tumor model, as this subtype of cancer showed hypered DNA replication stress response despite HR-proficiency. Thus, this provides us with an opportunity to evaluate DD-CIP2 activity in a HR-proficient context. We showed that DD-CIP2 treatment results in potent anti-tumor activity in vitro and significant tumor growth suppression in xenograft studies at well-tolerated doses, without evidence of substantial systemic toxicity.
Together, these findings establish CIP as a strategy for reprogramming DDR and overcoming limitations of current PARP inhibitor therapies in cancer, suggesting its potential for a broader clinical benefit.
利益披露 Disclosure
T. Qiu, None..
Y. Lee, None..
B. G. Dwyer, None..
Y. Tan, None..
T. Chen, None..
B. A. Romero, None..
Y. Wang, None..
J. Deng, None.
T. Zhang,
Matchpoint Therapeutics scientific founder, equity holder, and consultant.
Shenandoah Therapeutics equity holder.
G. R. Crabtree,
Foghorn Therapeutics founder and scientific adviser.
Shenandoah Therapeutics founder and scientific adviser.
S. M. Hinshaw, None.
K. Wong,
Tango Therapeutics consultant and/or has received Grant/Research support.
Janssen Pharmaceuticals consultant and/or has received Grant/Research support.
Pfizer consultant and/or has received Grant/Research support.
Bristol Myers Squibb consultant and/or has received Grant/Research support.
Zentalis Pharmaceuticals consultant and/or has received Grant/Research support.
Blueprint Medicines consultant and/or has received Grant/Research support.
Takeda Pharmaceuticals, consultant and/or has received Grant/Research support.
Mirati Therapeutics consultant and/or has received Grant/Research support.
Novartis consultant and/or has received Grant/Research support.
Genentech consultant and/or has received Grant/Research support.
Merus consultant and/or has received Grant/Research support.
Bridgebio Pharma consultant and/or has received Grant/Research support.
Xilio Therapeutics consultant and/or has received Grant/Research support.
Allorion Therapeutics consultant and/or has received Grant/Research support.
Boehringer Ingelheim consultant and/or has received Grant/Research support.
Cogent Therapeutics consultant and/or has received Grant/Research support.
Revolution Medicines consultant and/or has received Grant/Research support.
AstraZeneca consultant and/or has received Grant/Research support.
N. S. Gray,
Syros founder, science advisory board member (SAB) and equity holder.
C4 Therapeutics founder, science advisory board member (SAB) and equity holder.
Allorion Therapeutics founder, science advisory board member (SAB) and equity holder.
Light Horse Therapeutics founder, science advisory board member (SAB) and equity holder.
Voronoi founder, science advisory board member (SAB) and equity holder.
Matchpoint Therapeutics founder, science advisory board member (SAB) and equity holder.
Shenandoah Therapeutics founder, science advisory board member (SAB), equity holder and board member.
Larkspur founder, science advisory board member (SAB), equity holder and board member.
Soltego founder, science advisory board member (SAB), equity holder and board member.