Combination therapies using PRMT5 inhibitors for the treatment of cancer
Inventors
Engstrom, Lars Daniel • Olson, Peter • Christensen, James Gail
Assignees
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Publication Number
US-12171765-B2
Publication Date
2024-12-24
Expiration Date
Abstract
This disclosure relates to methods of treating cancer. This disclosure further relates to treating cancer in a subject with compounds that are inhibitors of PRMT5, particularly in combination with CDK4/6 inhibitors.
Core Innovation
The invention relates to a method for treating cancer in a subject by administering therapeutically effective amounts of palbociclib together with a compound of the formula or a pharmaceutically acceptable salt thereof. In particular embodiments, the compound is MRTX1719, described as an MTA-cooperative PRMT5 inhibitor, and the subject matter includes pharmaceutical composition and dosing frameworks for administering the palbociclib and the compound.
The disclosure describes PRMT5 and CDK4/6 inhibitor classes, including palbociclib as a CDK4/6 inhibitor. The rationale links sensitivity to PRMT5 inhibition to MTAP homozygous deletion, optionally with CDKN2A deletion, which is associated with elevated MTA, and describes MTA cooperatively sensitizing cells to PRMT5 inhibition when used with an MTA-cooperative PRMT5 inhibitor such as MRTX1719.
The document specifies broad cancer indications and also includes specific cancer types such as non-small cell lung cancer (NSCLC) and mesothelioma. The PRMT5 inhibitor structures are set out via multiple formula embodiments, including Formula IIA, Formula IIB, Formula IIC, and related larger formulas such as IIIC and IIIB, with combination cancer therapy framed as PRMT5 inhibitors together with CDK4/6 inhibitors.
Claims Coverage
The independent claim is a combination treatment method that uses two inventive elements: palbociclib and a compound of a specified formula (optionally as a pharmaceutically acceptable salt). Dependent claims further refine the second agent to MRTX1719, constrain palbociclib dosing quantitatively or relative to a clinically established therapeutic amount, specify sequential administration, and limit the treated cancer types.
Palbociclib with a compound of the formula for treating cancer
Administering to the subject a therapeutically effective amount of palbociclib and a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof to treat cancer.
MRTX1719 as an MTA-cooperative PRMT5 inhibitor in combination with palbociclib
Using MRTX1719 as the compound in the palbociclib combination, wherein MRTX1719 is an MTA-cooperative PRMT5 inhibitor.
Quantitatively constrained palbociclib dosing in mg/kg/day
Administering a therapeutically effective amount of palbociclib within about 0.01 to 300 mg/kg per day.
Palbociclib dose less than a fraction of a clinically established amount
Administering a therapeutically effective amount of palbociclib that is less than 50% of the clinically established therapeutic amount.
Sequential administration of palbociclib and MRTX1719
Administering palbociclib and MRTX1719 sequentially.
Treating non-small cell lung cancer (NSCLC) or mesothelioma
Applying the method to cancer that is non-small cell lung cancer (NSCLC) or mesothelioma.
Overall, the claim coverage is centered on treating cancer in a subject with therapeutically effective amounts of palbociclib together with a compound of a specified formula, with dependent claims particularly narrowing the second agent to MRTX1719, adding palbociclib dosing constraints, specifying sequential administration, and restricting the cancer indication to NSCLC or mesothelioma.
Stated Advantages
Greater antitumor activity for PRMT5 inhibitor plus CDK4/6 inhibitor than either alone across multiple tumor xenograft models.
Documented Applications
First-line treatment, first-line maintenance, and second-line treatment contexts including prior platinum/taxane chemotherapy.
Use in NSCLC or mesothelioma indications.
Use in MTAP-deleted cancers via MTA accumulation and selective targeting concept.
Tumor xenograft model testing with tumor volume measurement demonstrating combination benefit across lung and other tumor xenograft models.
Treating cancer in a subject, including embodiments for non-small cell lung cancer (NSCLC) or mesothelioma.
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