Small molecule GRB2 stabilizers for Ras map kinase inhibition
Inventors
AHMED, Zamal • Tainer, John A. • Jones, Darin E.
Assignees
The University of Texas System • University of Arkansas at Little Rock
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Publication Number
US-12599583-B2
Publication Date
2026-04-14
Expiration Date
Abstract
The present disclosure compounds of the formula (I-A) or (I), wherein the variables are defined herein, as well as pharmaceutical compositions thereof. The present disclosure also provides methods for the use of said compounds and/or pharmaceutical compositions, such as in the treatment of cancer. The present disclosure also provides methods for the use of compounds of the formula (III), wherein the variables are defined herein.
Core Innovation
The invention relates to compounds defined by one or more chemical formulae, including variable indices and substituent groups with n being 2, 3, 4, or 5, and X or Xa being O or S. The compound definitions include Ra, Rb, Rc, and Rd, together with alternative R1, R2, and R3 framework options, and further include halo, hydroxy, cyano, nitro, alkyl (C<=12), substituted alkyl (C<=12), alkoxy (C<=12), substituted alkoxy (C<=12), aralkyl (C<=12), heteroaryl (C<=12), heteroaralkyl (C<=12), and related substituted variants, as well as C(O)NR3aR3b and C(O)NR3cR3d forms and possible alkenediyl (C<=12) or substituted alkenediyl (C<=12) groupings.
The disclosure also presents specific example chemical structures, including GRB005–GRB030, GRB022 through GRB047, GRB039 through GRB064, GRB056–GRB081, GRB074 through GRB099, GRB091 through GRB121, GRB108–GRB140, GRB130 through GRB156, and GRB167–GRB189, as exemplars of the broader formula space. These structures show substituted aromatic, heteroaromatic, and fused-ring scaffolds with sulfur-containing groups, thiol or thio/thiol motifs, carbonyl-containing linkers, halogen and alkoxy substituents, and amide/urea-like carbonyls, while preserving the common scaffold definitions described in the formulas.
The invention is further linked to GRB2 stabilizers, including small-molecule compounds designed to stabilize dimeric GRB2. The disclosure states that stabilizing dimeric GRB2 inhibits Ras and downstream RTK signaling, and that the compounds are described in therapeutic and pharmaceutical contexts for cancer treatment and pharmaceutical compositions containing the compound with an excipient and/or pharmaceutically acceptable carrier.
Claims Coverage
The consolidated claim coverage includes broad formula-defined compound claims and therapeutic use/composition claim families. The independent claims together define variable chemical genera through alternative formula frameworks and optional pharmaceutically acceptable salts and/or tautomers, while associated claims add pharmaceutical compositions and treatment methods. Across the consolidated material, the inventive features total six core claim features.
Variable compound formula with defined substituent options
A compound of the formula wherein n is 2, 3, 4, or 5; Xa is O or S; Ra is hydrogen; Rb and Rc are each independently hydrogen, alkyl (C<=12), or substituted alkyl (C<=12); and Rd is independently halo, hydroxy, cyano, nitro, alkyl (C<=12), substituted alkyl (C<=12), alkoxy (C<=12), or substituted alkoxy (C<=12).
Alternative compound framework options including carbonyl-containing substituents
A compound of the formula wherein R1 is hydrogen or alkyl (C<=12), aralkyl (C<=12), heteroaralkyl (C<=12), or substituted versions; R2 is aralkyl (C<=12), heteroaryl (C<=12), heteroaralkyl (C<=12), or substituted versions; and R3 includes hydrogen, hydroxy, halo, amino, nitro, cyano, carboxy, mercapto, alkyl (C<=12), alkoxy (C<=12), alkylamino (C<=12), dialkylamino (C<=12), acyl (C<=12), acyloxy (C<=12), amido (C<=12), substituted versions, C(O)NR3aR3b, C(O)NR3cR3d, or R3 and R3' taken together as alkenediyl (C<=12) or substituted alkenediyl (C<=12).
Pharmaceutically acceptable salt and/or tautomer inclusion
A compound as defined in the formula claims, further including a pharmaceutically acceptable salt and/or tautomer of either of the formulae.
Pharmaceutical composition with excipient or carrier
A pharmaceutical composition comprising the compound together with an excipient or a pharmaceutically acceptable carrier.
Treatment methods using a compound that stabilizes dimeric GRB2
A method for treating ovarian, lung, or breast cancer by administering a therapeutically effective amount of a compound that stabilizes dimeric GRB2.
Cancer treatment subsets
The method for treating cancer wherein the cancer is KRAS-positive, and the method for treating triple negative breast cancer.
The claim coverage centers on broad chemical scaffold claims with extensive substituent variability and alternative formula frameworks, together with optional pharmaceutically acceptable salts and/or tautomers. The remaining claim coverage links these compounds to pharmaceutical compositions and to therapeutic methods for ovarian, lung, breast, KRAS-positive, and triple negative breast cancers in the context of stabilizing dimeric GRB2.
Stated Advantages
Stabilizes dimeric GRB2.
Inhibits Ras and downstream RTK signaling by stabilizing dimeric GRB2.
Inhibits RTK-induced MAP kinase signaling without altering RTK activity.
Produces cancer-cell effects with reported activity across cellular models including KRAS-mutant models and triple-negative breast cancer sensitivity.
Pharmacokinetic/pharmacological advantages over prior art.
Documented Applications
A method for treating ovarian, lung, or breast cancer by administering a therapeutically effective amount of a compound that stabilizes dimeric GRB2.
A method for treating cancer that is KRAS-positive by administering a therapeutically effective amount of a compound that stabilizes dimeric GRB2.
A method for treating triple negative breast cancer by administering a therapeutically effective amount of a compound that stabilizes dimeric GRB2.
A pharmaceutical composition including the compound together with an excipient or a pharmaceutically acceptable carrier.
Disease prevention/treatment using the disclosed GRB compounds as active pharmaceutical ingredients.
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