Acetyl-CoA synthetase 2 (ACSS2) inhibitors and methods using same
Inventors
Schug, Zachary • Salvino, Joseph • Yellamelli, Valli Venkata Srikanth
Assignees
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Publication Number
US-12281084-B2
Publication Date
2025-04-22
Expiration Date
Abstract
The present disclosure provides compounds, which in certain embodiments are ACSS2 inhibitors. In certain embodiments, the compounds of the disclosure are useful for treating, ameliorating, and/or preventing certain types of cancer.
Core Innovation
The invention provides ACSS2-targeting compounds of Formula (I), including enantiomers, diastereoisomers, tautomers, salts, and/or solvates thereof. The compounds are defined by specific connectivity and bond-order options for X1 and X2, together with extensive substituent definitions for R1a through R1g, R2, R3, R4, L, and R5.
The Formula (I) framework further includes the selection of R5 and the relationship to L, where the bond marked as * is to R5. R5 is selected from groups including C1-C10 alkyl, phenyl, and heteroaryl, with optional substitution lists, and the invention also encompasses embodiments where -L-R5 is optionally substituted heterocyclyl or optionally substituted heterocyclyl with a carbonyl-linked form as expressed in the formula definitions.
The invention additionally outlines therapeutic uses for diseases and conditions characterized by abnormal ACSS2 expression or abnormal ACSS2 activity. The documented therapeutic methods include cancer treatment, reducing non-metastatic-to-metastatic conversion, reducing hypoxic region development, and improving the effectiveness of chemotherapy, radiotherapy, and immunotherapy.
Claims Coverage
Independent claim coverage centers on a compound of Formula (I) with extensive structural variability, and dependent claims add specific formula embodiments and therapeutic method uses tied to ACSS2-associated disease endpoints. The covered inventive features include the X1/X2 bond-order framework, substituent selection across R1a through R1g, R2, R3, R4, the L linker, and R5, together with selected illustrated compound embodiments and use claims.
Compound of Formula (I) targeting ACSS2 inhibition
A compound of Formula (I), or an enantiomer, diastereoisomer, tautomer, salt, and/or solvate thereof, wherein X1 and X2 take one of two specified nitrogen/bond-order arrangements, with bond a and bond b set to the indicated double/single bond relationships, and wherein R1a, R1b, R1c, R1d, R1e, R1f, and R1g are independently selected from the recited substituent group; R2, R3, R4, L, and R5 are selected according to the recited option sets, including the defined linker selection for L with the bond marked as * being to R5 and the allowed substituent types for R5 or -L-R5.
Selected compound embodiments
The compound of Formula (I) is selected from specified illustrated compounds and example embodiments disclosed in the patent text.
ACSS2-associated disease treatment
A method for treating, ameliorating, or preventing a disease or disorder associated with abnormal expression or activity of ACSS2 by administering a therapeutically effective amount of the compound.
Reducing non-metastatic to metastatic conversion
A method to reduce the rate of, reverse, or prevent conversion of a non-metastatic cancer cell into a metastatic cancer cell by contacting the cell with an effective amount of the compound, optionally in vivo in a subject.
Combination use with chemotherapy, radiotherapy, or immunotherapy
A method for increasing the effectiveness of chemotherapy, radiotherapy, or immunotherapy in a cancer patient by administering a therapeutically effective amount of the compound together with at least one of those treatment modalities.
Reducing hypoxic region development
A therapeutic use directed to reducing hypoxic region development.
Overall, the claim coverage is grounded in a Formula (I) compound definition with fixed bond-order options and broad, explicitly enumerated substituent sets, while dependent claims further narrow to specific structural embodiments and therapeutic method claims focused on ACSS2-associated disease treatment and cancer-related process outcomes.
Stated Advantages
Treatment, amelioration, or prevention of a disease or disorder associated with abnormal expression or activity of ACSS2.
Reduces the rate of, reverses, or prevents conversion of a non-metastatic cancer cell into a metastatic cancer cell.
Improves the effectiveness of chemotherapy, radiotherapy, or immunotherapy in a cancer patient.
Reduces hypoxic region development.
Documented Applications
Treating, ameliorating, or preventing a disease or disorder associated with abnormal expression or activity of ACSS2 by administering a therapeutically effective amount of the compound.
Reducing the rate of, reversing, or preventing conversion of a non-metastatic cancer cell into a metastatic cancer cell by contacting the cell with an effective amount of the compound, optionally in vivo in a subject.
Increasing the effectiveness of chemotherapy, radiotherapy, or immunotherapy in a cancer patient by administering the compound together with at least one of those treatment modalities.
Reducing hypoxic region development.
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