Synthesis and Initial Evaluation of YM-08, a Blood-Brain Barrier Permeable Derivative of the Heat Shock Protein 70 (Hsp70) Inhibitor MKT-077, Which Reduces Tau Levels

Abstract

The molecular chaperone, heat shock protein 70 (Hsp70), is an emerging drug target for treating neurodegenerative tauopathies. We recently found that one promising Hsp70 inhibitor, MKT-077, reduces tau levels in cellular models. However, MKT-077 does not penetrate the blood-brain barrier (BBB), limiting its use as either a clinical candidate or probe for exploring Hsp70 as a drug target in the central nervous system (CNS). We hypothesized that replacing the cationic pyridinium moiety in MKT-077 with a neutral pyridine might improve its clogP and enhance its BBB penetrance. To test this idea, we designed and synthesized YM-08, a neutral analogue of MKT-077. Like the parent compound, YM-08 bound to Hsp70 in vitro and reduced phosphorylated tau levels in cultured brain slices. Pharmacokinetic evaluation in CD1 mice showed that YM-08 crossed the BBB and maintained a brain/plasma (B/P) value of ∼0.25 for at least 18 h. Together, these studies suggest that YM-08 is a promising scaffold for the development of Hsp70 inhibitors suitable for use in the CNS.

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

“…Indeed, this compound had superior anti-tau activity compared with other previously described Hsp70 inhibitors (Fig. 5A) (6,11,32,33). Importantly, tubulin levels were unchanged by Hsp70 inhibition.…”

“…The vital role of these proteins in many aspects of cellular functions has led to the development of small molecule inhibitors targeting chaperones for use as anti-cancer agents (1)(2)(3)(4) and therapeutics for neurodegenerative disorders (5)(6)(7)(8).…”

“…Hsc70 associates with both intact MTs (15)(16)(17)(18)(19) and tubulin directly through its nucleotidebinding domain (NBD), suggesting functional regulation of tubulin by Hsc70 beyond proteostasis (20). Hsc70 also interacts with the microtubule (MT)-associated protein (MAP) tau, a putative 'typical' client of Hsc70 (6,(21)(22)(23) further suggesting that Hsc70 uniquely regulates MT dynamics (24,25). In addition to its role in MT stability, abnormal tau accumulation is linked to the pathology of a number of neurodegenerative diseases including Alzheimer's disease (AD), frontotemporal dementia (FTD), Pick's disease and chronic traumatic encephalopathy (26).…”

“…Hsc70-mediated stabilization of tau levels may be relevant to tauopathies, as high levels of Hsc70 are found in brains of AD patients relative to other Hsp70 isoforms (30). Compounds that inhibit Hsp90 and Hsp70 family proteins reduce tau levels (6,11,(31)(32)(33) and rescue synaptic plasticity defects in tauopathy mouse models (33). Based on this evidence, we sought to determine why Hsc70 and tau are so intimately involved with each other and perhaps determine the most effective way to exploit this interaction for therapeutic intervention to treat tauopathies.…”

Mechanism of Inhibition for BMS-791325, a Novel Non-nucleoside Inhibitor of Hepatitis C Virus NS5B Polymerase

“…Binding of small molecules, such as BMS-791325, to the enzyme causes a shift in the interference pattern of incidence light that can be measured in real time (43,44). Both association and dissociation of BMS-791325 to/from WT, L30S, and P495L NS5B enzymes could be measured using this method.…”