US-12624035-B2 - Compounds for targeted protein degradation

US12624035B2US 12624035 B2US12624035 B2US 12624035B2US-12624035-B2

Abstract

This disclosure provides a compound of formula (III): or a pharmaceutically acceptable salt, solvate or derivative thereof, wherein the substituents are as defined herein. The disclosure also provides pharmaceutical compositions comprising said compounds and the use of said compounds in the treatment of diseases, e.g. cancer.

Inventors

David McGarry
Giles Albert Brown
Pauline DROUHIN

Assignees

AMPHISTA THERAPEUTICS LIMITED

Dates

Publication Date: 20260512
Application Date: 20250905
Priority Date: 20240906

Claims (2)

1 . A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:
2 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

Description

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY The content of the electronically submitted sequence listing (Name: 5700_0130003_SequenceListing_ST26.xml; Size: 2,170 bytes; Date of Creation: Sep. 4, 2025) submitted in this application is incorporated herein by reference in its entirety. FIELD The present disclosure relates to degradation of the Bromodomain-containing protein 9 (BRD9) protein. BRD9 has been linked to the proliferation of cancers, and the present disclosure relates to treatment of cancers, for example by BRD9 degradation. Specifically, the present disclosure relates to novel compounds that are useful in a targeted or selective degradation of BRD9, together with methods of preparing such molecules and therapeutic uses thereof. The present disclosure further relates to methods of treating cancer comprising the selective and/or targeted degradation of BRD9. BACKGROUND BRD9 is a protein encoded by the BRD9 gene on chromosome 5. BRD9 is a component of the BAF (BRG1- or BRM-associated factors) complex, a SWI/SNF ATPase chromatin remodeling complex, and belongs to family IV of the bromodomain-containing proteins (D. Hay et al., Med. Chem. Commun., 2015, 6, 1381-1386). SWI/SNF uses the energy of ATP hydrolysis to remodel chromatin and mobilize nucleosomes. SWI/SNF is implicated in activating transcription by remodelling nucleosomes, thereby permitting increased access of transcription factors for their binding sites. It is also required for transcriptional repression of some genes, and so controls transcription in various ways. Recurrent inactivating mutations in certain subunits of SWI/SNF complex have been identified in different cancers. Despite its known roles in tumour suppression, the mammalian SWI/SNF complex has recently received attention as a potential target for therapeutic inhibition (L. J. Martin et al., J. Med. Chem., 2016, 59, 4462-4475). Studies have shown that BRD9 is preferentially used by cancers that harbour SMARCB1 abnormalities such as malignant rhabdoid tumors and several specific types of sarcoma (X. Zhu, Y. Liao and L. Tang, Onco Targets Ther., 2020, 13, 13191-13200). 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 it is a therapeutic target for these lethal cancers. (Xiaofeng Wang et. al., Nature Communications, 2019, 10 (1881)). Recent studies highlight a role of BRD9 in leukemia growth: BRD9 was shown to be required for the proliferation of acute myeloid leukemia (AML) cells (Nature Chemical Biology, 2016, 101038/nchembio.2115). In addition to the role of BRD9 as a functional dependency in certain cancers, BRD9 also plays a pivotal role in immune cells as a regulator of regulatory T cells (Tregs) via transcriptional control of Foxp3 target genes, “BioRxiv, 10.1101/2020.02.26.964981. Because of BRD9's role in cancer proliferation there has been interest in the development of BRD9 inhibitors for the treatment of cancers including those described in: WO 2014/114721, WO 2016/077375, WO 2016/077378, WO 2016/139361, WO 2019/152440, a paper by Martin L. J. et. al., (Journal of Medicinal Chemistry 2016, 59, 4462-4475) titled “Structure-Based Design of an in Vivo Active Selective BRD9 Inhibitor”; a paper by Theodoulou N. H. et. al., (Journal of Medicinal Chemistry 2015, 59, 1425-1439) titled “Discovery of I-BRD9, a selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition”; and a paper by Clack P. et. al., (Angewandte Chemie, 2015, 127, 6315-6319). There is interest in the development of inhibitors or degraders that target BRD9 and not BRD4. Targeting BRD4 through genetic depletion, degradation or inhibition has significant effects on a diverse range of physiological functions including normal haematopoiesis, T cell viability and function, epidermal hyperplasia and homeostasis of different normal tissues in BRD4 genetically knocked out animals (Bolden et al Cell Rep. 2014; 8 (6): 1919-1929). In clinical trials, BRD4 inhibition has several dose limiting toxicities including fatigue, gastrointestinal symptoms, and thrombocytopenia, all of which have limited the efficacy of BRD4 inhibitors due to a small therapeutic window. (Mita et al. 2020. British Journal of Cancer 123, 1713-1714). Targeted Protein Degradation (TPD) is a therapeutic modality, which relies on the use of synthetic molecules to repurpose cellular degradation machinery to induce degradation of specific disease-causing proteins. TPD approaches offer a number of advantages over other drug modalities (e.g. small molecule inhibitors, antibodies & protein-based agents, antisense oligonucleotides & related knockdown approaches) including: potentiated pharmacology due to catalytic protein removal from within cells; abi