Compositions comprising bisfluoroalkyl-1,4-benzodiazepinone compounds for treating Adenoid Cystic Carcinoma
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Publication Number
US-12233072-B2
Publication Date
2025-02-25
Expiration Date
Abstract
The present invention provides methods of treating or suppressing Adenoid Cystic Carcinoma (ACC) or inhibiting ACC tumor growth in subjects by administering compositions comprising bisfluoroalkyl-1,4-benzodiazepinone compounds, including compounds of Formula (III) or prodrugs thereof.
Core Innovation
The invention provides pharmaceutical compositions that contain bisfluoroalkyl-1,4-benzodiazepinone compounds and substituted Notch-pathway-targeting small-molecule structures represented by Formula (I), Formula (III), and Formula V, together with salts and prodrugs. The compounds are characterized as Notch inhibitors and include variable substituents defined using R1, R2, R3, and R4, Ring A selected as phenyl or pyridinyl, and extensive substituent definitions.
The disclosure describes compositions comprising one or more selected compounds and methods of treating cancer by administering the disclosed compositions to suppress Adenoid Cystic Carcinoma (ACC) tumor growth or cause regression of an ACC tumor in a subject. The therapeutic use is tied to tumors that carry Notch-activating genetic alterations, including sequence variants in the NRR domain, the PEST domain, or both, gene rearrangements in the ectodomain of a Notch gene, and one or more of Notch1, Notch2, Notch3, or Notch4 mutations.
The treatment is presented for proliferative diseases and cancers, including ACC, and includes embodiments for monotherapy or combination therapy with an additional anti-cancer agent. Tumor growth suppression and tumor regression are expressed using tumor size reduction and tumor volume reduction, and the disclosure includes ACC histologic subtypes tubular ACC, cribriform ACC, and solid ACC.
Claims Coverage
The claim coverage centers on a method of suppressing ACC tumor growth or causing regression by administering a composition containing one or more disclosed Notch-pathway-targeting compounds, bisfluoroalkyl-1,4-benzodiazepinone compounds, or salts/prodrugs, where the ACC tumor comprises a Notch-activating genetic alteration. The consolidated claim coverage includes four principal inventive features, with dependent features specifying alteration types, Notch gene members, ACC histologic subtypes, and dose options.
Suppressing or regressing ACC tumors with Notch-activating genetic alterations
A method of suppressing Adenoid Cystic Carcinoma (ACC) tumor growth in a subject or causing regression of an ACC tumor in a subject, wherein the tumor comprises a Notch-activating genetic alteration by administering to the subject a composition comprising one or more compounds selected from the disclosed group, or salts thereof.
Notch-activating genetic alteration as a sequence variant in NRR and/or PEST domains
The method where the Notch-activating genetic alteration comprises a sequence variant in the NRR domain, the PEST domain, or both, of a Notch gene.
Notch-activating genetic alteration as an ectodomain gene rearrangement
The method where the Notch-activating genetic alteration comprises a gene rearrangement in the ectodomain of a Notch gene.
Notch-activating genetic alteration comprising Notch1 to Notch4 mutation(s)
The method where the Notch-activating genetic alteration comprises one or more of a Notch1, Notch2, Notch3, or Notch4 mutation, or a combination of such mutations.
Administering a specified dose range
The method where the composition is administered at a dose of 0.3, 0.6, 1.2, 2.4, or 8.4 mg.
Treating specific ACC histologic categories
The method where the ACC tumor consists of tubular ACC, cribriform ACC, or solid ACC.
The consolidated claim coverage is a Notch-activating genetic alteration-defined ACC treatment based on administration of disclosed compositions, with dependent coverage specifying alteration types, Notch gene members, dose options, and ACC histologic subtypes.
Stated Advantages
Suppressing Adenoid Cystic Carcinoma (ACC) tumor growth.
Causing regression of an ACC tumor.
Providing treatment in the presence of Notch-activating genetic alterations.
Treating proliferative diseases/cancers, including ACC.
Prolonging progression-free survival (PFS).
Prolonging overall survival (OS).
Reducing tumor size and tumor volume and suppressing tumor growth.
Documented Applications
Treatment of Adenoid Cystic Carcinoma (ACC) tumors in a subject with Notch-activating genetic alterations, including suppressing tumor growth and causing tumor regression.
Treatment of proliferative diseases/cancers, explicitly including ACC, associated with Notch-activating genetic alterations.
Therapy as monotherapy or combination therapy with an additional anti-cancer agent.
Use in ACC histologic subtypes tubular ACC, cribriform ACC, and solid ACC.
Combination treatment with an additional anti-cancer agent when the tumor lacks a Notch GOF mutation, including eribulin or vinorelbine.
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