Inhibitors of the notch transcriptional activation complex and methods for use of the same
Inventors
Capobianco, Anthony J. • Spyvee, Mark • Astudillo, Luisana • Orton, Darren
Assignees
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Publication Number
US-12275725-B2
Publication Date
2025-04-15
Expiration Date
Abstract
Disclosed herein are inhibitors of the Notch transcriptional activation complex, and methods for their use in treating or preventing diseases, such as cancer. The inhibitors described herein can include compounds of Formula (I) and pharmaceutically acceptable salts thereof: Formula (I), wherein the substituents are as described.
Core Innovation
The invention is directed to compounds of Formula (I), or pharmaceutically acceptable salts thereof, where n is 1 or 2, Y is O, S or NC1-3alkyl, Z is triazolyl, R1 is H or C1-3alkyl, R2 is H or C1-3alkyl, and R3 is C1-3alkyl or halophenyl. The disclosed approach centers on Notch pathway inhibitor compounds and the Notch transcriptional activation complex (NTC) as a therapeutic target.
The document describes the Notch transcriptional activation complex (NTC), including CSL, NICD, and MAML1, and relates NTC assembly to MAML1 recruitment and Notch target gene transcription. It further discloses inhibition of NTC activity, which decreases Notch target gene transcription.
The patent describes synthetic examples and analytical data for triazolyl-methoxy benzaldehyde framework compounds and related intermediates, including named final compounds NADi-351, NADi-355, and NADi-359. It also reports biological evaluation in an in vitro Notch complex assembly (NTC) assay workflow and cell-based and in vivo evaluation context.
Claims Coverage
The consolidated claim coverage includes two inventive features: one independent compound claim and one independent method claim. The claims are directed to Formula (I) compounds and to contacting a cell with the claimed compound or salt at an effective amount to inhibit NTC activity.
Compound of formula (i) with defined substituent variables
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 1 or 2; Y is O, S or NC1-3alkyl; Z is triazolyl; R1 is H or C1-3alkyl; R2 is H or C1-3alkyl; and R3 is C1-3alkyl or halophenyl.
Inhibiting the Notch transcriptional activation complex (NTC) in a cell with an effective amount
A method of inhibiting the Notch transcriptional activation complex (NTC) in a cell by contacting the cell with the compound or salt of Formula (I) at an effective amount to inhibit NTC activity.
Coverage is anchored in a defined chemical scaffold of Formula (I) with specified substituent variables and extends to a biological use method for inhibiting NTC activity in cells using that compound or salt at an effective amount.
Stated Advantages
Improved NTC potency for particular substituent combinations, as shown by NTC AlphaScreen IC50 comparisons.
Alkene methylation increases potency.
Improved metabolic stability is associated with alkene methylation.
Improved oral bioavailability is associated with alkene methylation.
Improved aqueous solubility for NADi-351 is reported using solubility measurements in simulated gastric fluid and fasted-state simulated intestinal fluid.
The acid metabolite for certain ester analogs does not show NTC assembly inhibition.
Inhibit NTC and decrease Notch target gene transcription.
Potentially disrupt MAML1 recruitment.
Nanomolar potency.
Up to 100% bioavailability.
Superior metabolic stability.
Selective Notch1 complex inhibition as described in assays/models.
Documented Applications
Inhibition of the Notch transcriptional activation complex (NTC) in a cell by contacting the cell with the claimed compound or salt at an effective amount to inhibit NTC activity.
Notch inhibition / Notch1 activity with downstream effects including tumor sphere viability and Notch target gene expression.
Use in PDX models in NSG mice showing tumor volume effects, alongside a reported lack of goblet cell metaplasia assessed by periodic acid-Schiff (PAS) stain.
Treating cancer, including T-ALL, B-ALL, breast cancer, medulloblastoma, colorectal cancer, NSCLC, melanoma, CADASIL, CLL, HCC, CMML, PDAC, multiple sclerosis, HNSCC, renal cell adenocarcinoma, and gastric/esophageal cancers.
Treating Tetralogy of Fallot (TOF).
Treating Alagille syndrome.
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