Orally Bioavailable Cyclin A/B RxL Inhibitors: Optimization of a Novel Class of Macrocyclic Peptides That Target E2F-High and G1–S-Checkpoint-Compromised Cancers

Cyclins A and B bind and activate their cognate cyclin-dependent
kinase (CDK) to regulate progression through the S and G2/M phases
of the cell cycle, respectively. Cyclins recruit substrates and regulators
through the binding of an RxL motif with a Hydrophobic Patch (HP)
on the cyclin surface. We recently disclosed the first class of passively
permeable macrocyclic peptides that bind to the HP of both Cyclin
A and Cyclin B and selectively kill cancer cells with high E2F activity.
We used a lead example to demonstrate in vivo tumor
regression in cell-line-derived xenograft models of small-cell lung
cancer (SCLC) via intraperitoneal dosing. Here we describe the optimization
of this series for drug-like properties and oral bioavailability,
resulting in the discovery of a lead compound, which demonstrates
tumor regression in CDX models of SCLC via oral dosing. We are currently
evaluating Cyclin A/B inhibition in a Phase 1 clinical trial.

细胞周期蛋白A与B可分别结合并激活其对应的细胞周期蛋白依赖性激酶（cyclin-dependent kinase, CDK），进而调控细胞周期S期与G2/M期的进程。细胞周期蛋白可通过其表面的疏水补丁（Hydrophobic Patch, HP）与RxL基序结合，从而招募底物与调控因子。本团队近期首次报道了一类可被动通透细胞膜的大环肽，该类肽能够同时结合细胞周期蛋白A与B的疏水补丁位点，并选择性杀伤E2F活性高的癌细胞。我们以一款先导化合物为实例证实，经腹腔给药可在小细胞肺癌（SCLC）的细胞系源异种移植（cell-line-derived xenograft, CDX）模型中实现体内肿瘤消退。本文针对该系列化合物开展了成药性与口服生物利用度优化，最终得到一款先导化合物，其经口给药后可在小细胞肺癌细胞系源异种移植模型中实现肿瘤消退。目前我们正在一项I期临床试验中评估细胞周期蛋白A/B抑制疗法的效果。