KRAS G12V mutant binds to JAK1, inhibitors, pharmaceutical compositions, and methods related thereto
Inventors
Fu, Haian • Mo, Xiulei • TANG, CONG
Assignees
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Publication Number
US-12577278-B2
Publication Date
2026-03-17
Expiration Date
Abstract
This disclosure relates to the discovery that a G12V mutant of KRAS (hereinafter KRAS G12V) binds to JAK1, i.e., the existence of a KRAS G12V and JAK1 binding interaction. In certain embodiments, this disclosure relates to methods of disrupting the KRAS G12V and JAK1 interaction reversing KRAS G12V induced immune escape by cancer cells utilizing agents that prevent the binding of JAK1 to KRAS G12V.
Core Innovation
The invention addresses a KRAS G12V–JAK1 interaction in which KRAS G12V directly binds JAK1. A peptide RasKi is disclosed that disrupts the KRAS G12V–JAK1 interaction, including a peptide consisting of the amino acid sequence MDYKDDEG (SEQ ID NO:1) or ADYKDDEG (SEQ ID NO:2), and X1DYKDDEG derivatives. The binding site is mapped to an 8-mer in the JAK1 pseudokinase domain containing Lys606.
Experimental support is provided that RasKi restores IFNγ/JAK/STAT signaling, including STAT1/STAT3 phosphorylation and increased IRF1, TAP1, and PD-L1 expression. The restored signaling is described as reversing KRAS G12V–mediated immune escape, thereby enhancing cancer cell killing by IFNγ, NK cells, and engineered NY-ESO-1 CD8+ T cells.
Therapeutic use is described for treating cancers with a KRAS G12V mutation by administering the disclosed peptide RasKi to a subject in need thereof. Broader agent formats are also described, including peptide/small molecule/antibody formats and conjugation to E3 ubiquitin ligase binders for degradation and PROTAC-like approaches, together with combination therapy using immune checkpoint inhibitors and other chemotherapeutics.
Claims Coverage
The independent claim covers one core therapeutic method using a RasKi peptide sequence to treat a KRAS G12V-mutant cancer; the claim set includes dependent refinements that specify combination components and optional peptide conjugation.
Treating KRAS G12V-mutant cancer with MDYKDDEG or ADYKDDEG peptide RasKi
A method of treating a cancer with a KRAS G12V mutation by administering an effective amount of a peptide consisting of the amino acid sequence MDYKDDEG (SEQ ID NO:1) or ADYKDDEG (SEQ ID NO:2) to a subject in need thereof.
The claims primarily cover administration of the specified RasKi peptide sequences for treating KRAS G12V-mutant cancer, with dependent claim refinements directed to combination therapy with specified immune checkpoint inhibitors and optional conjugation to an E3 ubiquitin ligase binder.
Stated Advantages
Restores IFNγ/JAK/STAT signaling, including STAT1/STAT3 phosphorylation.
Reverses KRAS G12V–mediated immune escape.
Enhances cancer cell killing by IFNγ, NK cells, and engineered NY-ESO-1 CD8+ T cells.
Documented Applications
Treating a cancer with a KRAS G12V mutation by administering RasKi peptides MDYKDDEG (SEQ ID NO:1) or ADYKDDEG (SEQ ID NO:2).
Combination therapy with an immune checkpoint inhibitor selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, atezolizumab, durvalumab, or avelumab (or combinations thereof).
Conjugating the peptide to an E3 ubiquitin ligase binder.
The method is applied to colon cancer (as one specified example).
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