SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Jun. 23, 2021, is named 127353-0108_SL.txt and is 16,958 bytes in size.

BACKGROUND

Neurodegenerative diseases affect an estimated 50 million Americans each year, exacting an incalculable personal toll and an annual economic cost of hundreds of billions of dollars in medical expenses and lost productivity. Synucleinopathies are neurodegenerative diseases characterized by the abnormal accumulation of α-synuclein (α-Syn) aggregates in neurons and glial cells.

α-Synuclein is a 140 amino acid protein preferentially expressed in neurons at pre-synaptic terminals where it is thought to play a role in regulating synaptic transmission (Bendor et al., Neuron 2013; 79:1044-66). α-Synuclein can form pathological aggregates in neurons known as Lewy bodies, which are characteristic of both Parkinson's Disease (PD) and dementia with Lewy bodies (DLB). The pathological aggregates consist of aggregated, insoluble accumulations of misfolded α-synuclein proteins in neurons, nerve fibers or glial cells and are a characteristic feature of synucleinopathies. Synucleinopathies include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), the Lewy body variant of Alzheimer's disease (LBVAD), combined Parkinson's disease (PD) and Alzheimer's disease (AD), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). In PD and DLB, α-Syn aggregates are in the neuronal cytoplasm and axonal processes into Lewy bodies and Lewy neurites, respectively, whereas α-Syn inclusions in oligodendroglia are the recognized neuropathologic hallmarks of MSA.

There is currently a lack of therapeutics that target synucleinopathies from the perspective of α-synuclein aggregation. Strategies aimed at reducing α-synuclein aggregation possess therapeutic potential in the treatment of patients with synucleinopathies.

SUMMARY

The present disclosure stems from the recognition that a bispecific conjugate compound that includes an E3 ubiquitin ligase binding moiety that is based on an imide drug (e.g., lenalidomide, thalidomide, VHL ligand) and also includes a binder of α-synuclein may induce proteasome degradation of α-synuclein aggregates. The disclosure therefore provides compounds, compositions, and methods for the treatment of various neurodegenerative diseases associated with α-synuclein aggregates based on this discovery. The bispecific conjugate compounds described herein degrade the α-synuclein aggregates by removing α-synuclein aggregates or reducing the degree of α-synuclein aggregation to low levels in a cellular model and/or animal model, thereby possessing therapeutic potential in the treatment of patients with synucleinopathies including but not limited to Parkinson's disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA).

The present disclosure also provides methods to remove α-synuclein aggregation or reduce Lewy bodies or α-synuclein aggregate in a patient having Lewy body disease or risk of Lewy body disease, and methods to reduce dementia with Lewy bodies (DLB) or multiple system atrophy (MSA) or other synucleinopathies.

One aspect of the present disclosure is a compound of Formula A,
EBM-L-SBM  (Formula A)
wherein

EBM is an E3 ubiquitin ligase binding moiety;

L is a linker covalently attached to EBM and SBM; and

SBM is an α-synuclein protein binding moiety of the formula:


or a pharmaceutical acceptable salt, an enantiomer, a non-enantiomer, a tautomer, a racemate, a solvate, a metabolic precursor, a prodrug thereof,

wherein


is covalently linked to L; and

(i)


is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N;


is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and


is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; or

(ii)


is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N;


is a substituted or unsubstituted monocyclic aromatic ring containing 0 to 2 ring heteroatoms selected from O, S, and N; and


is a substituted or unsubstituted bicyclic fused aromatic ring containing at least 1 ring heteroatom selected from O, S, and N.

Another aspect of the disclosure is a compound of any one of the Formula (I)-(VI):


or pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof, wherein L1, L2, L3, X, Y, J, Q, K, T, U, V, Z, Y1, R′, R″, R′″, R2′, R3′, n, m, k and m6 are as defined herein.

Another aspect of the present disclosure is a composition comprising a compound of the disclosure, and a pharmaceutically acceptable excipient.

Another aspect of the present disclosure is a method of treating, lessening the severity of, delaying the progression of, reducing the risk of developing, and/or delaying the onset of a disease characterized by the presence of Lewy bodies or pathological aggregates of α-synuclein, the method comprising administering to a subject in need thereof an effective amount of a compound or a composition of the present disclosure.

Another aspect of the present disclosure is a method for synthesizing the compounds of the disclosure.

The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative embodiments and features described herein, further aspects, embodiments, objects and features of the disclosure will become fully apparent from the drawings and the detailed description and the claims.

