Novel Compounds for Targeted Degradation of BRD9 and Their Use for Treating Cancer

Important Compound Classes

Title

Compounds for Targeted Degradation of BRD9

Patent Publication Number

WO 2021/178920 A1

Publication Date

September 10, 2021

Priority Application

US 62/985,774 and US 62/061,659

Priority Date

March 5, 2020 and August 5, 2020

Inventors

Nasveschuk, C. G.; Zeid, R.; Yin, N.; Jackson, K. L.; Veits, G. K.; Moustakim, M.; Yap, J. L.

Assignee Company

C4 Therapeutics Inc., USA

Disease Area

Cancer

Biological Target

BRD9

Summary

Bromodomain-containing proteins (BRD) such as BRD9 are proteins that recognize acylated lysine residues such as those on the N-terminals of histones. BRDs are evolutionarily conserved and present in diverse nuclear proteins comprising HATs (GCN5, PCAF), ATP-dependent chromatin-remodeling complexes (BAZ1B), helicases (SMARCA), methyltransferases (MLL, ASH1L), transcriptional coactivators (TRIM/TIF1, TAFs), transcriptional mediators (TAF1), nuclear-scaffolding proteins (PB1), and the BET family. Bromodomain-containing proteins have several functions that relate to transcription mediation and coactivation; therefore, they are involved in cellular proliferation.

Studies have shown that BRD9 is preferentially used by cancers that harbor SMARCB1 abnormalities such as malignant rhabdoid tumors and several specific types of sarcomas. BRD9-containing complexes bind to both active promoters and enhancers, where they contribute to gene expression. Loss of BRD9 results in gene expression changes related to apoptosis regulation, translation, and development regulation. BRD9 is essential for the proliferation of SMARCB1-deficient cancer cell lines, suggesting that it is a therapeutic target for these lethal cancers. BRD9 is also a critical target required in acute myeloid leukemia. Research has also been reported on protein-degrading compounds that have an E3 ligase binding portion and a BRD9 binding portion wherein the BRD9 binding ligand binds to BRD9 and brings it to the ligase for ultimate degradation by the proteasome.

The present application describes a series of compounds that degrade bromodomain-containing protein 9 (BRD9) via the ubiquitin proteasome pathway (UPP). The compounds include “targeting ligand” that binds to BRD9, an E3 ligase binding portion (typically via a cereblon subunit), and a linker that covalently links the targeting ligand to the E3 ligase binding portion. The targeting ligand is a moiety B of the formulas (I) to (VI); the linker is a moiety L, and the remainder of a molecule is the E3 ligase binding portion and particularly BRD9 degraders for the treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X₃, X₄, X₅ and X₆ = N, CH and CR₃, wherein no more than 3 of X₃, X₄, X₅ and X₆ are N;

X₇ = N or CH;

X₈ and X₉ = N and CH, wherein at least one of X₈ and X₉ is CH;

X₁₂ = a 5-membered heteroaryl group with 1, 2, or 3 atoms selected from N, O and S, wherein X₁₂ is optionally substituted with 1, 2, or 3 groups selected from R₃;

X₁₇ = aryl, heteroaryl, bicycle or cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents selected from R₃;

Q₁ = NH, N(alkyl), N(haloalkyl), CH₂, O and S, wherein if X₇ is N, then Q₁ is CH₂;

R = H, C₁–C₄haloalkyl, C₁–C₄alkyl, F, Cl, Br, I, CH₂F, CHF₂, CF₃, CH₂Cl, CHCl₂, CCl₃, CH₂Br, CHBr₂ and CBr₃;

R₁ = H, C₁–C₄alkyl, C₁–C₄haloalkyl, or cycloalkyl;

B = B₁ and B₂; L = a bivalent linking group;

a = 0, 1 or 2; and y = 0, 1 or 2.

Key Structures

Biological Assay

The BRD9 protein degradation assay was performed using the HiBiT method. The compounds described in this application were tested for their ability to degrade BRD9. The BRD9 DC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for BRD9 degradation. The biological data obtained from testing representative examples are listed in the following table.

For DC₅₀: “+++” means <100 nM; “++” means 100–500 nM; “+” means 500–800 nM.

Claims

Total claims: 182

Compound claims: 177

Pharmaceutical composition claims: 1

Method for treatment claims: 2

Use of compound claims: 2

Recent Review Articles

• 1.Gokani S.; Bhatt L. K.. Eur. J. Pharmacol. 2021, 911, 174523.
• 2.D’Amico F.; Mukhopadhyay R.; Ovaa H.; Mulder M. P. C.. ChemBioChem. 2021, 22, 2011.
• 3.Coughlan A. Y.; Testa G.. Int. J. Cancer 2021, 149, 1732.
• 4.Tsuda M.; Fukuda A.; Kawai M.; Araki O.; Seno H.. Cancer Sci. 2021, 112, 490.
• 5.Zhu X.; Liao Y.; Tang L.. OncoTargets Ther. 2020, 13, 13191.
• 6.Bechter O.; Schoffski P.. Pharmacol. Ther. 2020, 208, 107479.

The author declares no competing financial interest.

Special Issue

Published as part of the ACS Medicinal Chemistry Letters virtual special issue “New Drug Modalities in Medicinal Chemistry, Pharmacology, and Translational Science”.