Fibroblast modulators in stroma-rich tumors
OwnerChristian STEVENS, Bart ROMAN +2inventors
InventorsChristian STEVENS, Bart ROMAN, Christophe MANGODT, Olivier DE WEVER
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Abstract
The present invention relates to the field of oncology and provides compounds, compositions, uses and methods for treating cancer, in particular stroma rich tumors, by selectively targeting cancer associated fibroblasts (CAFs). CAF targeting is one strategy for enhancing immunotherapy efficacy and may improve patient response rates. In addition, by this specificity in targets and associated pathways, the damaging of normal tissue is reduced.
Claims14
A compound of Formula I or a salt, hydrate, or solvate thereof, for use in the treatment of invasive lobular breast carcinoma, tumors having a Tumor-Stroma Ratio (TSR) of >50%;
- and/or pancreatic ductal adenocarcinoma;
- wherein
- represents a single or double bond;
- each of said R1, R1′ and R1″ is independently selected from the group consisting of —H, -halo, —CF3, —OCF3, and —OC1-3alkyl;
- R2 is selected from the group consisting of —H, -halo, —CF3, —OCF3, and —OC1-3alkyl;
- R3 is selected from the group consisting of —H, -halo, —C1-3alkyl and —CF3;
- or R2 and R3 together with the C atoms to which they are attached form a 6-membered aromatic or non-aromatic heterocycle;
- R4 is selected from the group consisting of —H, -halo, —CF3, —OCF3, and —OC1-3alkyl;
- each of said R5, R5′ and R5″ is independently selected from the group consisting of —H, —OH, —CN, —C1-3alkyl, —OC1-3alkyl, —NR6R7, —S02—NH2, —SO2-iPr, -Het1 and -halo;
- each of said —C1-3alkyl and —OC1-3alkyl being optionally substituted with from 1 to 3 substituents selected from the group consisting of ═O, —NR8R9, and -Het1;
- R6, R7, R8 and R9 are selected from the group consisting of —H, and —C1-3alkyl;
- each of said —C1-3alkyl being optionally substituted with from 1 to 3 substituents selected from the group consisting of ═O, —NH2, and —NH-iPr,
- Het1 is a 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from S, O and N;
- wherein each of said Het1 is optionally substituted with from 1 to 3 substituents selected from the group consisting of —C1-3alkyl, —OC1-3alkyl, —C1-3alkyl-OH and —OC1-3alkyl-OH;
- wherein at least one of said R1, R1′ and R1″ is —OC1-3alkyl or —CF3;
- wherein when R2 and R3 do not form a heterocycle then represents a double bond.
A compound or a salt, hydrate, or solvate thereof, selected from the list comprising:
A compound for use as an anti-invasive compound of tumor cells in a subject having cancer;
- said compound being represented by any one of formula (IIa) or (IIb)
- wherein
- each of said R1, R1′ and R1″ is independently selected from the group consisting of —H, -halo, —CF3, —OCF3, and —OC1-3alkyl;
- R4 is selected from the group consisting of —H, -halo, —CF3, —OCF3, and —OC1-3alkyl;
- each of said R5, R5′ and R5″ is independently selected from the group consisting of —H, —OH, —CN, —C1-3alkyl, —OC1-3alkyl, —NR6R7, —SO2—NH2, —SO2-iPr, -Het1 and -halo;
- each of said —C1-3alkyl and —OC1-3alkyl being optionally substituted with from 1 to 3 substituents selected from the group consisting of ═O, —NR8R9, and -Het1;
- R6, R7, R8 and R9 are selected from the group consisting of —H, and —C1-3alkyl;
- each of said —C1-3alkyl being optionally substituted with from 1 to 3 substituents selected from the group consisting of ═O, —NH2, and —NH-iPr,
- Het1 is a 5- or 6-membered heterocycle having from 1 to 3 heteroatoms selected from S, O and N;
- wherein each of said Het1 is optionally substituted with from 1 to 3 substituents selected from the group consisting of —C1-3alkyl, —OC1-3alkyl, —C1-3alkyl-OH and —OC1-3alkyl-OH;
- wherein at least one of said R1, R1′ and R1″ is —OC1-3alkyl or —CF3.
Dependencies are inferred from the claim text.