Targeting KRAS Mutant Cancers via Combination Treatment: Discovery of a 5‑Fluoro-4-(3H)‑quinazolinone Aryl Urea pan-RAF Kinase Inhibitor

Optimization of a series of aryl
urea RAF inhibitors led to the
identification of type II pan-RAF inhibitor GNE-0749 (7), which features a fluoroquinazolinone hinge-binding motif. By minimizing
reliance on
common polar hinge contacts, this hinge binder allows for a greater
contribution of RAF-specific residue interactions, resulting in exquisite
kinase selectivity. Strategic substitution of fluorine at the C5 position
efficiently masked the adjacent polar NH functionality and increased
solubility by impeding a solid-state conformation associated with
stronger crystal packing of the molecule. The resulting improvements
in permeability and solubility enabled oral dosing of 7. In vivo evaluation of 7 in combination with the MEK
inhibitor cobimetinib demonstrated synergistic pathway inhibition
and significant tumor growth inhibition in a KRAS mutant xenograft
mouse model.

一系列芳基脲类RAF抑制剂优化过程导致了一种新型II型广谱RAF抑制剂GNE-0749（7）的发现，该抑制剂具有氟喹诺酮酮类铰链结合基序。通过最小化对常见极性铰链接触的依赖，此铰链结合剂能够促进RAF特异性残基相互作用的更大贡献，从而实现卓越的激酶选择性。在C5位置的战略性氟取代有效地掩盖了邻近的极性NH官能团，并通过阻碍与分子晶体堆积更强相关的固态构象，提高了溶解度。这些在渗透性和溶解度方面的改进使得7能够通过口服给药。7与MEK抑制剂考比替尼的体内联合评估显示了协同途径抑制以及在KRAS突变异种移植小鼠模型中显著的肿瘤生长抑制。