Barlaam Bernard, Cosulich Sabina, Degorce Sébastien, Ellston Rebecca, Fitzek Martina, Green Stephen, Hancox Urs, Lambert-van der Brempt Christine, Lohmann Jean-Jacques, Maudet Mickaël, Morgentin Rémy, Plé Patrick, Ward Lara, Warin Nicolas
IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom.
IMED Oncology, AstraZeneca, Darwin Building, Cambridge Science Park, 319 Milton Road, Cambridge CB4 0WG, United Kingdom.
Bioorg Med Chem Lett. 2017 May 1;27(9):1949-1954. doi: 10.1016/j.bmcl.2017.03.027. Epub 2017 Mar 14.
Attempts to lock the active conformation of compound 4, a PI3Kβ/δ inhibitor (PI3Kβ cell IC 0.015μM), led to the discovery of a series of 8-(1-phenylpyrrolidin-2-yl)-6-carboxamide-2-morpholino-4H-chromen-4-ones, which showed high levels of potency and selectivity as PI3Kβ/δ inhibitors. Compound 10 proved exquisitely potent and selective: PI3Kβ cell IC 0.0011μM in PTEN null MDA-MB-468 cell and PI3Kδ cell IC 0.014μM in Jeko-1 B-cell, and exhibited suitable physical properties for oral administration. In vivo, compound 10 showed profound pharmacodynamic modulation of AKT phosphorylation in a mouse PTEN-null PC3 prostate tumour xenograft after a single oral dose and gave excellent tumour growth inhibition in the same model after chronic oral dosing. Based on these results, compound 10 was selected as one of our PI3Kβ/δ preclinical candidates.
对PI3Kβ/δ抑制剂（PI3Kβ细胞IC为0.015μM）化合物4的活性构象进行锁定的尝试，促成了一系列8-(1-苯基吡咯烷-2-基)-6-羧酰胺-2-吗啉代-4H-色烯-4-酮的发现，这些化合物作为PI3Kβ/δ抑制剂表现出高水平的效力和选择性。化合物10被证明具有极高的效力和选择性：在PTEN缺失的MDA-MB-468细胞中PI3Kβ细胞IC为0.0011μM，在Jeko-1 B细胞中PI3Kδ细胞IC为0.014μM，并且具有适合口服给药的物理性质。在体内，化合物10在单次口服给药后对小鼠PTEN缺失的PC3前列腺肿瘤异种移植模型中的AKT磷酸化表现出显著的药效学调节作用，并且在慢性口服给药后在同一模型中产生了优异的肿瘤生长抑制效果。基于这些结果，化合物10被选为我们的PI3Kβ/δ临床前候选药物之一。
