Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.).
Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)
J Pharmacol Exp Ther. 2024 Jan 2;388(1):171-180. doi: 10.1124/jpet.123.001919.
Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by a motor disorder with combinations of dystonia, parkinsonism, and spasticity, leading to premature death. PKAN is caused by mutations in the gene that result in loss or reduction of PANK2 protein function. PANK2 is one of three kinases that initiate and regulate coenzyme A biosynthesis from vitamin B5, and the ability of BBP-671, an allosteric activator of pantothenate kinases, to enter the brain and elevate coenzyme A was investigated. The metabolic stability, protein binding, and membrane permeability of BBP-671 all suggest that it has the physical properties required to cross the blood-brain barrier. BBP-671 was detected in plasma, liver, cerebrospinal fluid, and brain following oral administration in rodents, demonstrating the ability of BBP-671 to penetrate the brain. The pharmacokinetic and pharmacodynamic properties of orally administered BBP-671 evaluated in cannulated rats showed that coenzyme A (CoA) concentrations were elevated in blood, liver, and brain. BBP-671 elevation of whole-blood acetyl-CoA served as a peripheral pharmacodynamic marker and provided a suitable method to assess target engagement. BBP-671 treatment elevated brain coenzyme A concentrations and improved movement and body weight in a PKAN mouse model. Thus, BBP-671 crosses the blood-brain barrier to correct the brain CoA deficiency in a PKAN mouse model, resulting in improved locomotion and survival and providing a preclinical foundation for the development of BBP-671 as a potential treatment of PKAN. SIGNIFICANCE STATEMENT: The blood-brain barrier represents a major hurdle for drugs targeting brain metabolism. This work describes the pharmacokinetic/pharmacodynamic properties of BBP-671, a pantothenate kinase activator. BBP-671 crosses the blood-brain barrier to correct the neuron-specific coenzyme A (CoA) deficiency and improve motor function in a mouse model of pantothenate kinase-associated neurodegeneration. The central role of CoA and acetyl-CoA in intermediary metabolism suggests that pantothenate kinase activators may be useful in modifying neurological metabolic disorders.
泛酸激酶相关神经变性（PKAN）的特征是运动障碍，伴有肌张力障碍、帕金森病和痉挛，导致过早死亡。PKAN 是由 基因的突变引起的，导致 PANK2 蛋白功能的丧失或减少。PANK2 是三种激酶之一，它启动并调节辅酶 A 从维生素 B5 合成，研究了泛酸激酶别构激活剂 BBP-671 进入大脑并提高辅酶 A 的能力。BBP-671 的代谢稳定性、蛋白结合和膜通透性都表明它具有穿过血脑屏障的物理特性。BBP-671 在啮齿动物口服给药后可在血浆、肝脏、脑脊液和大脑中检测到，表明 BBP-671 能够穿透大脑。在有套管的大鼠中评估口服给予 BBP-671 的药代动力学和药效学特性表明，辅酶 A（CoA）浓度在血液、肝脏和大脑中升高。BBP-671 升高全血乙酰辅酶 A 可作为外周药效标志物，并提供了一种评估靶标结合的合适方法。BBP-671 治疗可提高 PKAN 小鼠模型大脑辅酶 A 浓度，改善运动和体重。因此，BBP-671 穿过血脑屏障纠正 PKAN 小鼠模型中的大脑 CoA 缺乏，导致运动改善和存活，为 BBP-671 作为 PKAN 潜在治疗方法的开发提供了临床前基础。意义声明：血脑屏障是针对大脑代谢的药物的主要障碍。本工作描述了泛酸激酶激活剂 BBP-671 的药代动力学/药效学特性。BBP-671 穿过血脑屏障纠正神经元特异性辅酶 A（CoA）缺乏，并改善泛酸激酶相关神经变性小鼠模型的运动功能。CoA 和乙酰辅酶 A 在中间代谢中的核心作用表明，泛酸激酶激活剂可能在修饰神经代谢疾病方面有用。
