US-12622901-B2 - Compounds for tau protein degradation

Abstract

Provided herein are bifunctional compounds that bind tau protein and/or promote targeted ubiquitination for the degradation of tau protein. In particular, provided are compounds that can bind tau protein, a protein whose aggregation is implicated in a variety of neurodegenerative disease (e.g., tauopathies), and can promote its degradation by recruiting an E3 ubiquitin ligase (e.g., Cereblon), which can ubiquitinate tau protein, marking it for proteasomal degradation. Also provided are radiolabeled forms of the bifunctional compounds, pharmaceutical compositions comprising the bifunctional compounds, methods of detecting and/or diagnosing neurological disorders, methods of detecting and/or diagnosing pathological aggregation of tau protein (e.g., in the central nervous system), methods of treating and/or preventing neurological disorders, and methods of promoting the degradation of tau protein by E3 ubiquitin ligase activity in a subject by administering a compound or composition described herein.

Inventors

• Nathanael S. Gray
• Stephen J. Haggarty
• Quan CAI
• Tinghu Zhang
• Maria Catarina Telo Baptista Lima da Silva
• Fleur M. Ferguson

Assignees

• DANA-FARBER CANCER INSTITUTE, INC.
• THE GENERAL HOSPITAL CORPORATION

Dates

Publication Date

20260512

Application Date

20230523

Claims (13)

1. 1 . A compound having a structure: or a pharmaceutically acceptable salt thereof.
2. 2 . A radiolabeled compound comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, enriched with a radionuclide.
3. 3 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
4. 4 . A method of treating a neurological disorder in a subject in need thereof, the method comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the subject in need thereof.
5. 5 . The method of claim 4 , wherein the neurological disorder is a neurodegenerative disease.
6. 6 . The method of claim 5 , wherein the neurodegenerative disease is a tauopathy.
7. 7 . The method of claim 6 , wherein the tauopathy is primary age-related tauopathy (PART)/neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy, dementia pugilistica, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Huntington's disease, Alzheimer's disease, or argyrophilic grain disease.
8. 8 . A method of promoting the degradation of tau protein in a subject in need thereof, the method comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the subject in need thereof.
9. 9 . A method of detecting a neurological disorder, the method comprising contacting a compound of claim 2 , or a pharmaceutically acceptable salt thereof, with a tissue.
10. 10 . A method of detecting pathological aggregation of tau protein, the method contacting a compound of claim 2 , or a pharmaceutically acceptable salt thereof, with a tissue.
11. 11 . A method of diagnosing a neurological disorder in a subject, the method comprising contacting a compound of claim 2 , or a pharmaceutically acceptable salt thereof, with a tissue of the subject.
12. 12 . The method of claim 9 , wherein the tissue is tissue of the central nervous system.
13. 13 . The method of claim 12 , wherein the tissue of the central nervous system is brain tissue.

Description

RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 16/630,294, filed on Jan. 10, 2020, which is a national stage application, filed under 35 U.S.C. § 371, of International Application No. PCT/US2018/041787, filed Jul. 12, 2018, which claims the benefit of priority under 35 U.S.C. § 119 (e) to U.S. Provisional Application, U.S. Ser. No. 62/531,773, filed Jul. 12, 2017, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention relates generally to bifunctional compounds that bind tau protein and promote its degradation via recruitment of an E3 ubiquitin ligase, and uses of the compounds in the treatment of neurological diseases (e.g., Alzheimer's disease). BACKGROUND OF THE INVENTION Alzheimer's disease (AD) is characterized by progressive loss of memory and other mental functions. Worldwide, nearly 35 million people suffer from AD. The exact mechanism for AD is not fully understood, but two characteristic protein deposits, senile plaques and neurofibrillary tangles (NFT), have been defined as causative events for AD. While senile plaques include extracellular aggregation of amyloid-β peptides (Aβ), the NFTs are composed of hyperphosphorylated tau protein. Since tau accumulation begins before extensive neuronal loss, targeting tau protein has become a strategy for treating AD. Hence, tau is not only a drug target but also a biomarker for early diagnosis of AD by measurement of brain tau loading. Positron emission tomography (PET) is a molecular imaging technique that provides a non-invasive diagnostic method for the detection of tau aggregation. Thus, several tau radiotracers have been developed and tested in humans. Recently, a new therapeutic strategy to reduce and/or eliminate proteins associated with certain pathological states, PROTAC (proteolysis targeting chimeras; e.g., see U.S. patent application U.S. Ser. No. 14/792,414, filed Jul. 6, 2015), was developed by creating bifunctional compounds that recruit target proteins to E3 ubiquitin ligases, which subsequently induce proteasome-mediated degradation of the target protein. E3 ubiquitin ligases are proteins that, in combination with an E2 ubiquitin-conjugating enzyme, promote the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond (e.g., an amide bond that is not present on the main chain of a protein). The ubiquitination of the protein commonly results in degradation of the target protein by the proteasome. Currently, there are no clinically approved compounds that target tau for the treatment of AD, and overall clinical failure is much higher for AD compared to other diseases. Accordingly, an ongoing need exists to identify drugs that effectively treat neurological disorders, such as AD. In particular, drugs that can take advantage of cellular machinery involved in protein homeostasis (e.g., ubiquitination and proteasome degradation) may find use as therapeutic agents. SUMMARY OF THE INVENTION PROTAC relies on a strategy of recruiting target protein to an E3 ubiquitin ligase and subsequently inducing proteasome-mediated degradation of the target protein. The present disclosure describes the conjugation of tau binding moieties with an E3 ubiquitin ligase binding moiety (e.g., lenalidomide, thalidomide) to provide compounds that can induce the ubiquitination of tau protein and promote its degradation in cells. Accordingly, the present disclosure stems from the recognition that the aggregation of tau protein, in particular hyperphosphorylated tau protein, causes certain neurological disorders (e.g., tauopathies such as AD), and that by targeting both tau protein, or any post-translationally modified form of tau, and recruiting an E3 ubiquitin ligase (e.g., Cereblon) to ubiquitinate the tau protein and mark it for proteasome degradation, a single bifunctional compound can promote the degradation of tau protein, thus providing new compounds, compostions, and methods for the treatment of neurological disease (e.g., tauopathies such as AD). Thus, the present disclosure represents an important advance in the treatment of neurological disease, particularly tauopathies. In one aspect, provided are compounds of Formula I: or pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, wherein: T is a tau protein binding moiety;E is an E3 ubiquitin ligase binding moiety;L is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted heteroalkylene, a bond, —O—, —N(RA)—, —S—, —C(═O)—, —C(═O)O—, —C(═O)NRA—, —NRAC(═O)—, —NRAC(═O)RA—, —C(═O)RA— —NRAC(═O)O—, —NRAC(═O)N(RA)—, —OC(═O)—, —OC(═O)O—,