Novel Heteroaryl Compounds as Splicing Modulators for Modulating Splicing of mRNA and Uses Thereof for Treating Diseases

Important Compound Classes

Title

Methods for Modulating Splicing

Patent Publication Number

WO 2020/257184 A1

Publication Date

December 24, 2020

Priority Application

US 62/862,468; US 16/813,069

Priority Date

June 17, 2019; March 9, 2020

Inventors

Luzzio, M.; McCarthy, K.; Liu, B.

Assignee Company

Skyhawk Therapeutics Inc., USA

Disease Area

Cancers and noncancers, include but not limited to, cystic fibrosis, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, cardiomyopathies, ischemic heart disease, pain, α- or β-thalassemia

Biological Target

mRNA

Summary

The majority of protein-coding genes in the human genome are composed of multiple exons (coding regions) that are separated by introns (noncoding regions). Gene expression results in a single precursor mRNA (pre-mRNA). The intron sequences are subsequently removed from the pre-mRNA by a process called splicing, which results in mature mRNA (mRNA). By including different combinations of exons, alternative splicing gives rise to multiple mRNAs encoding distinct protein isoforms. The spliceosome, an intracellular complex of multiple proteins and ribonucleoproteins, catalyzes splicing.

Current therapeutic approaches to direct and control mRNA expression require methods such as gene therapy, genome editing, or a wide range of oligonucleotide technologies (antisense, RNAi, etc.). Gene therapy and genome editing act upstream of transcription of mRNA by influencing the DNA code and thereby changing mRNA expression. Oligonucleotides modulate the action of RNA via canonical base/base hybridization.

Another potential therapeutic approach to modulate the action of RNA is using small molecules. Small molecules have been essential in uncovering the mechanisms, regulations, and functions of many cellular processes, including DNA replication, transcription, and translation. This approach offers benefits such as easy administration (e.g., oral administration), easy penetration into cell membranes or target organs, and better absorption. In addition, RNA secondary structure can be annotated from its sequence, thus allowing identification of functional regions that could be targeted by small molecule. Targeting the RNA transcriptome with small-molecule modulators represent an untapped therapeutic approach to treat a variety of RNA-mediated diseases by modulating splicing.

The present application describes a series of novel heteroaryl compounds as splicing modulators that bind and modulate splicing of mRNA and uses thereof in treating various diseases. Further, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

A = N or CR_A;

ring Q = aryl, monocyclic heteroaryl or fused bicyclic heteroaryl;

X = −NR₃, −CR₄R₅–, −C(=O)–, −S–, −S(=O)–, −S(=O)₂–, or −(S=O)(=NR₁)–;

Z = N or CR₇;

a, b, and c = 0, 1 or 2;

R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, and R₁₇ = H, F, −OR₁, substituted or unsubstituted C₁–C₆ alkyl, substituted or unsubstituted C₁–C₆ fluoroalkyl, and substituted or unsubstituted C₁–C₆ heteroalkyl; and

R and R₁₃ = taken in combination form a substituted or unsubstituted C₁–C₆ alkylene group.

Key Structures

Biological Assay

The Target 1 splicing potency assay and Target 2 splicing potency assay were performed. The small molecules splicing modulators (compounds) described in this application were tested. The Target 1 splicing potency WT IC₅₀ (nM), E7b EC₅₀ (nM), and E7c EC₅₀ values (nM) are shown in Table 1. The Target 2 splicing potency WT IC₅₀ (nM) and E12c EC₅₀ values (nM) are shown in Table 2.

Biological Data

Tables 1 and 2 below show representative compounds (small molecules splicing modulators, SMSMs) tested for Target 1 splicing potency and Target 2 splicing potency, respectively. The biological data obtained from testing representative examples are listed in the following Tables.

Claims

Total claims: 110

Method of treatment claims: 106

Method of inducing claims: 1

Method of modulating splicing claims: 2

Method of decreasing protein expression claims: 1

Recent Review Articles

• 1.Alroy I.; Mansour W.; Klepfish M.; Sheinberger Y.. Drug Discovery Today 2021, 26, 786.
• 2.Angelbello A. J.; Chen J. L.; Disney M. D.. Ann. N. Y. Acad. Sci. 2020, 1471, 57.
• 3.Zhang D., Meng F.. ChemMedChem 2020, 15, 2098.
• 4.Zhu S.; Rooney S.; Michlewski G.. Int. J. Mol. Sci. 2020, 21, 2996.
• 5.Boer R. E.; Torrey Z. R.; Schneekloth J. S. Jr.. ACS Chem. Biol. 2020, 15, 808.
• 6.Costales M. G.; Childs-Disney J. L.; Haniff H. S.; Disney M. D.. J. Med. Chem. 2020, 63, 8880.

The author declares no competing financial interest.