Deuterated compounds for restoring mutant p53 function
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Publication Number
US-11963953-B2
Publication Date
2024-04-23
Expiration Date
Abstract
The compounds of the current disclosure include propynyl substituted indoles, where one or more hydrido radicals is substituted with a deuterium atom, wherein the compound binds a mutant p53 protein and increases wild-type p53 activity of the mutant p53 protein.
Core Innovation
The invention concerns a composition comprising a population of molecules having a mass of at least 1 μg, wherein at least 10% of the molecules each independently comprise a deuterium atom, and each molecule is a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The disclosed embodiments define the compounds of Formula (I) with substituent selections for R1, R2, R3, and R4, including deuterated options among the listed substituent groups.
The structural framework includes broad allowable substituent diversity, with independent definition options for each of R21 and R22, while disclosed embodiments state that R3 is H and R4 is heterocyclyl substituted with one, two or three substituents selected from the listed groups. The partial content also identifies deuterated analogs and isotopic enrichment, including deuterated methoxy, trideuteriomethoxy, and trideuterio(iodo)methane motifs.
The compounds are positioned as p53 Y220C binding agents and are linked in the partial content to functional performance described by an HTRF/TR-FRET in vitro DNA binding assay used to calculate SC150 values. The disclosure also frames deuteration in relation to stability, metabolism-related performance, and increased exposure.
Claims Coverage
Two independent claims are present. The claims coverage centers on composition claims requiring a defined molecular population, minimum mass, and minimum fraction of molecules containing deuterium or the specified structure.
Deuterated molecule population with mass and fraction constraints
A composition comprising a population of molecules having a mass of at least 1 μg, wherein at least 10% of the molecules in the population each independently comprise a deuterium atom, and each molecule is a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Structured compound population with minimum fraction constraints
A composition comprising a population of molecules having a mass of at least 1 μg, wherein at least 10% of the molecules in the population are a compound with the specified structure, or a pharmaceutically acceptable salt thereof.
The claims coverage is composition-focused and combines defined Formula (I) structural features with quantitative population requirements. Related claim content also ties the compounds to p53 Y220C functional and assay-linked thresholds, including SC150 in an HTRF assay.
Stated Advantages
Improved metabolic stability.
Increased primate plasma AUC0-24.
Reduced glucuronidation versus hydrogen analogs.
Increased DNA binding and downstream tumor-suppressive effects, including apoptosis.
Documented Applications
Treating cancer in a subject by administering a therapeutically effective amount of the composition, where a compound of Formula (I) shows an SC150 value for p53 Y220C less than 1 mM measured by an HTRF assay.
Cancer treatment methods described as inducing apoptosis via binding to p53 mutant Y220C and reconformation.
Nonclinical pharmacokinetic study in male cynomolgus monkeys comparing a deuterated compound versus a comparator.
In vitro mass-spectrometry characterization to determine deuterated and non-deuterated fractions.
In vitro HTRF/TR-FRET DNA binding assay using recombinant His-tagged p53 Y220C to calculate SC150 values.
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