Manley Paul W, Huth Felix, Moussaoui Saliha, Schoepfer Joseph
Disease Area Oncology, Global Discovery Chemistry, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.
Pharmacokinetic Sciences, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland.
Bioorg Med Chem Lett. 2022 Mar 1;59:128577. doi: 10.1016/j.bmcl.2022.128577. Epub 2022 Jan 19.
The ubiquitously expressed ABL1 and ABL2 protein kinases play many important roles in cell function. Although they have been implicated in neuron development, maintenance and signaling, there are no good tool compounds to evaluate the effects of ABL kinase inhibition in the brain. Asciminib is a recently approved drug that specifically and potently inhibits the tyrosine kinase activity of ABL1, ABL2 and that of the chimeric BCR-ABL1 oncoprotein which causes chronic myeloid leukemia. Herein we show that asciminib does not penetrate the intact blood-brain barrier (BBB) following administration to rats, which curtails its utility for assessing the in vivo effects of ABL kinase inhibition in the brain. However, we describe another specific ABL kinase inhibitor, possessing physicochemical characteristics suitable for BBB penetration, and which after administration (either i.v., i.p. or p.o.) to mice achieves substantial, pharmacologically relevant brain concentrations. This bipyridine compound (4) therefore has potential for elucidating the role of ABL kinases in the brain in non-clinical studies.
广泛表达的ABL1和ABL2蛋白激酶在细胞功能中发挥着许多重要作用。尽管它们与神经元发育、维持和信号传导有关，但目前尚无良好的工具化合物来评估ABL激酶抑制在大脑中的作用。阿伐替尼是一种最近获批的药物，它能特异性且强效地抑制ABL1、ABL2以及导致慢性髓性白血病的嵌合BCR-ABL1癌蛋白的酪氨酸激酶活性。在此我们表明，给大鼠给药后，阿伐替尼不会穿透完整的血脑屏障（BBB），这限制了其用于评估ABL激酶抑制在大脑中的体内作用。然而，我们描述了另一种特异性ABL激酶抑制剂，其理化特性适合穿透血脑屏障，给小鼠静脉注射、腹腔注射或口服后，能在大脑中达到可观的、具有药理学相关性的浓度。因此，这种联吡啶化合物（4）在非临床研究中具有阐明ABL激酶在大脑中作用的潜力。
