Novel PRMT5 Inhibitors for Treating Cancer

Important Compound Classes

Title

Novel PRMT5 Inhibitors

Patent Publication Number

WO 2021/163344 A1

Publication Date

August 19, 2021

Priority Application

US 62/975,258

Priority Date

February 12, 2020

Inventors

Allen, J. R.; Amegadzie, A.; Beylkin, D. J.; Booker, S.; Bourbeau, M. P.; Butler, J. R.; Frohn, M. J.; Glad, S. O. S.; Husemoen, B. W.; Kaller, M. R.; Kohn, T. J.; Lanman, B. A.; Li, K.; Liu, Q.; Lopez, P.; Ma, V. V.; Manoni, F.; Medina, J.; Minatti, A. E.; Peiro Cadahia, J.; Pettus, L.; Pickrell, A. J.; Sarvary, I.; Tamayo, N. A.; Vestergaard, M.

Assignee Company

Amgen, Inc., USA

Disease Area

Cancer

Biological Target

PRMT5

Summary

Epigenetic regulation of gene expression is an important biological determinant of protein production, cellular differentiation and plays a significant pathogenic role in several human diseases. Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence. Typically, epigenetic regulation is mediated by selective and reversible modification. (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin. These covalent modifications can be controlled by enzymes such as methyltransferases (e.g., protein arginine N-methyltransferase 5 (PRMT5)), many of which are associated with specific genetic alterations that can cause human disease. PRMT5 plays a role in diseases such as proliferative disorders, metabolic disorders, and blood disorders.

The homozygous deletion of tumor suppressor genes is a key driver of cancer, frequently resulting in the collateral loss of passenger genes located in close genomic proximity to the tumor suppressor. Deletion of these passenger genes can create therapeutically tractable vulnerabilities that are specific to tumor cells. Deletion of MTAP (methylthioadenosine phosphorylase), a key enzyme in the methionine and adenine salvage pathways, results in accumulation of its substrate, methylthioadenosine (MTA). MTA shares close structural similarity to S-adenosylmethionine (SAM), the substrate methyl donor for the type II methyltransferase PRMT5. Targeting PRMT5 with an MTA-cooperative small molecule inhibitor could preferentially target the MTA bound state of PRMT5, enriched in MTAP null tumor cells, while providing an improved therapeutic index over normal cells where MTAP is intact and MTA levels are low.

The present application describes a series of novel PRMT5 inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

  represents a single or double bond;

X₁ and X₂ = N or C, wherein if X₁ is C, it can be optionally substituted with halo or C_1–6alkyl;

Ar = six membered aromatic ring having 0–2 N atoms, wherein each Ar is independently substituted with 0–2 R_a groups;

R = H or methyl;

R₁ and R₂ = H, optionally substituted with C_1–6alkyl, C_1–6alkynyl, -C(OR_c), single and double cyclyl having 0–3 N, S or O atoms, wherein substituents are selected from halo, optionally substituted with C_1–6alkyl, −C(O)NR_fR_g, OH and 5-membered ring having 0–3 N atoms; and

R₃ and R₄ = H, halogen, alkynyl, cyano and C_1–6alkyl, optionally substituted with halo or deuterium.

Key Structures

Biological Assay

The HTC116 MTAP null proliferation assay was performed. The compounds described in this application were tested for their ability to inhibit PRMT5. The PRMT5 IC₅₀ (μM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for PRMT5 inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 25

Compound claims: 19

Pharmaceutical composition claims: 2

Method of treatment claims: 4

Recent Review Articles

• 1.Guccione E.; Schwarz M.; Di Tullio F.; Mzoughi S.. Curr. Opin. Pharmacol. 2021, 59, 33.
• 2.Lei Y.; Han P.; Tian D.. Transl. Oncol. 2021, 14, 101194.
• 3.Tang Z.; Xu Z.; Zhu X.; Zhang J.. Cancer Commun. 2021, 41, 16.
• 4.Pellarin I.; Belletti B.; Baldassarre G.. Med. Res. Rev. 2021, 41, 586.
• 5.Verheul T. C. J.; Trinh V. T.; Vazquez O.; Philipsen S.. ChemMedChem. 2020, 15, 2436.
• 6.Sengupta S.; Kennemer A.; Patrick K.; Tsichlis P.; Guerau-de-Arellano M.. Trends Immunol. 2020, 41, 918.

The author declares no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters special issue “Epigenetics 2022”.