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-12128048-B2
Publication Date
2024-10-29
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 KRASG12C inhibitors.
Core Innovation
The disclosed subject matter relates to PRMT5 inhibitors and a KRAS G12C inhibitor in combination cancer therapy. The combination includes administering a therapeutically effective amount of adagrasib and a therapeutically effective amount of a compound of the formula, or a pharmaceutically acceptable salt.
The disclosure particularly emphasizes treating cancers associated with MTAP homozygous deletion, with or without a KRAS G12C mutation and with or without CDKN2A homozygous deletion. The rationale provided links MTAP loss to elevated MTA, where MTA inhibits PRMT5 and creates selective dependency.
The patent describes PRMT5 inhibitor embodiments, including compounds having a compound formula (IIIA), specific PRMT5 inhibitor structures including MRTX1679, MRTX9768/MRTX77477, and MRTX1719, and pharmaceutically acceptable salts. It also refers to MTA-cooperative PRMT5 inhibitors and PRMT5 activity, including methylosome protein 50 (MEP50) and histone H2A/H4 methyltransferase activity.
The patent states preclinical xenograft study design and results demonstrating improved antitumor activity for a PRMT5 inhibitor plus a KRAS G12C inhibitor versus either agent alone. The reported results are described in KRAS G12C and CDKN2A/MTAP-deleted lung tumor models, with tumor-volume tables reported across examples including LU99, LU99 PRMT5-041, and SW1573 PRMT5-044.
Claims Coverage
The independent claims cover three principal inventive features in lung cancer: co-administration of adagrasib with a compound of the formula, reducing tumor volume, and slowing tumor growth.
Adagrasib with compound of the formula for treating lung cancer
Administering to the subject a therapeutically effective amount of adagrasib and a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof.
Adagrasib with compound of the formula for reducing tumor volume
Administering to the subject a therapeutically effective amount of adagrasib and a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof to reduce tumor volume.
Adagrasib with compound of the formula for slowing tumor growth
Administering to the subject a therapeutically effective amount of adagrasib and a therapeutically effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof to slow tumor growth.
Lung cancer with MTAP homozygous deletion in the adagrasib combination treatment
Applying the method of the adagrasib combination treatment to lung cancer characterized by a homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene.
Lung cancer with CDKN2A homozygous deletion in the adagrasib combination treatment
Further including lung cancer having a homozygous deletion of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene.
PRMT5 inhibitor dosing range in the adagrasib combination treatment
Administering the method of the adagrasib combination treatment in which a PRMT5 inhibitor is provided at a dosage ranging from about 0.01 to 300 mg/kg per day.
Sub-50% dosing constraint for the PRMT5 inhibitor in the adagrasib combination treatment
Using a PRMT5 inhibitor at a therapeutically effective amount that is less than 50% of the clinically established therapeutic amount.
Sequential administration of adagrasib and MRTX-1719
Providing that adagrasib and MRTX-1719, or a salt of MRTX-1719, are administered sequentially.
The claim coverage centers on combination administration of adagrasib with a compound of the formula or a pharmaceutically acceptable salt, with dependent features specifying lung-cancer subsets defined by MTAP and CDKN2A homozygous deletions, PRMT5-inhibitor dosing constraints, and sequential administration involving MRTX-1719.
Stated Advantages
Improved antitumor activity of a PRMT5 inhibitor plus a KRAS G12C inhibitor versus either agent alone in KRAS G12C and CDKN2A/MTAP-deleted lung tumor models.
Documented Applications
Treating lung cancer in a subject by administering adagrasib together with a compound of the formula or a pharmaceutically acceptable salt thereof.
Reducing tumor volume in a subject suffering from lung cancer using adagrasib together with a compound of the formula or a pharmaceutically acceptable salt thereof.
Slowing tumor growth in a subject suffering from lung cancer using adagrasib together with a compound of the formula or a pharmaceutically acceptable salt thereof.
Preclinical xenograft study in KRAS G12C and CDKN2A/MTAP-deleted lung tumor models, reporting tumor-volume tables for examples including LU99, LU99 PRMT5-041, and SW1573 PRMT5-044.
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