Compounds useful in the treatment of disorders associated with mutant RAS
Inventors
Rabbitts, Terrence • QUEVEDO, Camilo • Bataille, Carole
Assignees
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Publication Number
US-11970469-B2
Publication Date
2024-04-30
Expiration Date
Abstract
The present invention relates to compounds of Formula I as defined herein, and salts and solvates thereof. (I) The present invention also relates to pharmaceutical compositions comprising compounds of Formula (I), and to compounds of Formula (I) for use in the treatment of proliferative disorders, such as cancer, as well as other diseases or conditions in which inhibition of a RAS-effector protein-protein interaction is implicated.
Core Innovation
The invention relates to compounds of Formula Ih, Ii, Ij or Ik, including salts or solvates thereof. The compounds are defined by substituent variables R1, R2, R3, R4, R5, R6, R7a, R7b, R8 and R9, where each variable is selected from specified chemical groups. The scope includes related chemical forms such as polymorphs, N-oxides, tautomers, isomers, prodrugs and metabolites.
The compounds are intended to inhibit RAS-effector protein-protein interactions, notably RAS with RAF and PI3K. The patent positions this inhibition as relevant to treatment of mutant RAS-mediated proliferative disorders, including cancer.
The disclosure also includes pharmaceutical compositions comprising the compounds together with pharmaceutically acceptable excipients, and therapeutic uses such as inhibiting RAS-effector PPI and treating proliferative disorders or cancer. The provided material further references combination therapy concepts, including surgery, radiotherapy, chemotherapy, immunotherapy, gene therapy and antisense therapies.
Claims Coverage
The claim set centers on one independent claim covering Formula Ih, Ii, Ij or Ik compounds, including salts and solvates, with position-specific substituent selections. Dependent claims refine R1, R2/R3, R4 and R9 scope and add a pharmaceutical composition context, giving six inventive features in the consolidated coverage.
Formula Ih/Ii/Ij/Ik compound scaffold with defined substituents
A compound of Formula Ih, Ii, Ij or Ik, or a salt or solvate thereof, wherein R1, R2, R3, R4, R5, R6, R7a, R7b, R8 and R9 are defined by specified selection rules from the enumerated chemical groups.
Pharmaceutical composition including compound of Formula Ih/Ii/Ij/Ik
A pharmaceutical composition including a compound of claim 1, together with a pharmaceutically acceptable salt or solvate of the compound, and one or more pharmaceutically acceptable excipients.
Restricted R1 substituent selection
A compound of Formula Ih, Ii, Ij or Ik, or a salt or solvate thereof, where R1 is selected from C1-3 alkoxy and NRpRq.
Restricted R2 and R3 substituent selection
A compound of Formula Ih, Ii, Ij or Ik, or a salt or solvate thereof, where R2 and R3 are each independently selected from hydrogen, halogen, and C1-6 alkyl.
Restricted R4 substituent selection
A compound of Formula Ih, Ii, Ij or Ik, or a salt or solvate thereof, where R4 is selected to be either hydrogen or methyl.
Specific R9 substituent pattern with NMe2
A compound of Formula Ih, Ii, Ij or Ik, or a salt or solvate thereof, where R9 is a C1-6 alkyl group substituted with NMe2.
The consolidated claim coverage is anchored on the Formula Ih/Ii/Ij/Ik compound scaffold, including salts and solvates, with extensive substituent-variable definitions. The independent scaffold claim is refined by dependent selections for R1, R2/R3, R4 and R9, and by a pharmaceutical composition including excipients.
Stated Advantages
Intracellular antibody-derived compound Abd-7 reduces DLD-1 cell viability after 72 hours, with an IC50 of 8.2 μM.
Examples 1–33 show improved potency versus Abd-7 for reducing DLD-1 cell viability after 72 hours, with reported IC50 values of 5.3 μM, 7.2 μM, and 4.5 μM.
Reference compounds Abd-2 and PPIN-2 do not affect DLD-1 cell viability across the tested concentrations.
Documented Applications
Compound screening using KRAS(G12V) GST fusion proteins in SPR with CM5 chips, Biacore T200, and DCAI as a positive control at 100 μM, with outcomes summarized in a table of SPR/BRET/viability results.
BRET2/RAS biosensor assays summarized together with SPR and cell viability results for multiple numbered examples.
DLD1 cell viability assays summarized together with SPR/BRET outcomes for multiple numbered examples.
Use in a DLD-1 cell viability evaluation over 72 hours using IC50 measurements for an intracellular antibody-derived compound (including Abd-7 and Examples 1–33) and comparison to reference compounds Abd-2 and PPIN-2, with results shown in Table 1.
Inhibiting RAS-effector protein-protein interactions, including RAS with RAF and PI3K.
Treatment of mutant RAS-mediated proliferative disorders, including cancer.
Combination therapy concepts including surgery, radiotherapy, chemotherapy, immunotherapy, gene therapy and antisense therapies.
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