LBPO.CH01 · 化学 · Late-Breaking
DNA damage chemical inducers of proximity (DD-CIP) for targeted cancer therapy
作者与单位
摘要 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.