New Directions in Antibacterial, Anticancer, and Gene Editing Therapies

Abstract

Recent advancements in pharmaceutical and gene therapy research have led to the development of novel compounds and delivery systems that target critical areas of unmet medical needs, including drug-resistant bacterial infections, cancer, and genetic diseases. This Patent Highlight reviews the key findings from three recent patents that describe innovations in tricyclic quinolone compounds and adeno-associated virus (AAV) vectors for gene editing. These innovations demonstrate significant progress in the treatment of antibiotic-resistant bacterial infections, BCL6-dependent cancers, and the efficient delivery of CRISPR-based gene editing tools.

Important Compound Classes

Titles

Tricyclic Quinolone BCL6 Bifunctional Degraders; Single Cell Co-sequencing of DNA Methylation and RNA; and AAV Vectors for Gene Editing

Patent Publication Numbers

WO 2023/240039 A1 (URL: https://patents.google.com/patent/WO2023240038A1/en?oq=WO+2023%2f240038+A1);

WO 2023/239907 A1 (URL: https://patents.google.com/patent/WO2023239907A1/en?oq=WO+2023%2f239907+A1);

WO 2023/240162 A1 (URL: https://patents.google.com/patent/WO2023240162A1/en?oq=WO+2023%2f240162+A1)

Publication Dates

December 14, 2023

Priority Applications

US 63/501,080; US 63/350,603; US 63/350,376

Priority Dates

May 9, 2023; June 9, 2022; June 8, 2022

Inventors

Obeng, K. M.; Hansen, J. D.; Correa, M. D.; Lajiness, J. P.; Leverson, J. D.; Marone, T. J.; McNeill, M. H.; Nagy, M. A.; Schleicher, K. D.; Valiere, A.; Yang, M. (WO 2023/240039 A1); Lam, H.; Richards, A.; Zhang, K. (WO 2023/239907 A1); Deiter, F.; Zhou, W.; Baney, K.; Colin, I. Foruny, C.; Wright, A.; Staahl, B. T.; Higgins, S.; Oakes, B.; Makhija, S.; Denny, S.; Mohr, M. (WO 2023/240162 A1)

Assignee Companies

Treeline Biosciences, Inc. [US/US], 677 Washington Blvd, Suite 525, Stamford, Connecticut 06901, United States (WO 2023/240039 A1); The Regents of the University of California [US/US], 1111 Franklin Street, 5th Floor, Oakland, California 94607-5200, United States (WO 2023/239907 A1); Scribe Therapeutics Inc. [US/US], 1150 Marina Village Parkway, Alameda, California 94501, United States (WO 2023/240162 A1)

Disease Area

Bacterial infections, cancer, and genetic diseases

Biological Target

Bacterial DNA processes, BLC6 protein and specific genetic Loci.

Summary

The emergence of antibiotic-resistant bacterial strains, the persistence of difficult-to-treat cancers, and the challenges in delivering gene editing machinery have driven the development of new therapeutic strategies. Tricyclic quinolones and AAV vectors represent promising solutions in these fields. This Patent Highlight provides a review of three patents that present novel approaches in these domains.

The patent application WO 2023240039 A1 describes a novel tricyclic quinolone compound specifically targeting resistant bacterial strains, such as MRSA and MDR Pseudomonas aeruginosa. The compound inhibits bacterial DNA gyrase and topoisomerase IV, enzymes essential for DNA replication and repair, leading to bacterial cell death. The aim is to develop an antibacterial agent with enhanced efficacy against drug-resistant strains, addressing the critical issue of antibiotic resistance. The compounds demonstrated superior antibacterial activity compared to existing quinolones, with favorable pharmacokinetic properties, including good oral bioavailability and metabolic stability.

The patent application WO 2023239907 A1 pertains to a tricyclic quinolone compound designed for cancer therapy, particularly targeting the BCL6 protein involved in the pathogenesis of lymphomas. The compound acts as a bifunctional inhibitor, disrupting both the DNA-binding domain and the protein–protein interaction interface of BCL6, leading to apoptosis in BCL6-dependent cancer cells.

The invention pertains to a therapeutic agent that effectively inhibits BCL6, providing a new treatment option for resistant cancers. The compounds showed potent anticancer activity, significantly reducing tumor size in preclinical models and demonstrating minimal off-target effects.

Finally, the patent application WO 2023240162 A1 discusses adeno-associated virus (AAV) vectors engineered for gene editing applications, particularly in treating genetic diseases. The vectors deliver CRISPR-CasX systems to target cells, inducing specific DNA modifications through NHEJ or HDR, depending on the application. To invention pertains to the development of safe and efficient AAV-based delivery systems for CRISPR gene editing, enhancing therapeutic potential by improving targeting specificity and minimizing off-target effects. The AAV vectors demonstrated high efficiency in editing target loci with minimal off-target effects and favorable safety profiles in preclinical assays.

As such, the patents reviewed in this Patent Highlight reflect significant advancements in the fields of antibacterial therapy, cancer treatment, and gene editing. The tricyclic quinolones and AAV vectors described herein offer new hope for treating drug-resistant infections, challenging cancers, and genetic disorders. Continued research and development in these areas are expected to further enhance therapeutic outcomes and expand the scope of these innovative treatments.

Key Structures

Biological Assay

In vitro binding assays confirm binding affinity to BCL6. HiBiT based degradation assay. Cell proliferation assays evaluated antiproliferative effects on cancer cells. In vivo efficacy studies assess tumor reduction and survival rates. Toxicity studies evaluated safety and tolerability.

Biological Data

The table below provides Y_min and EC₅₀ values for exemplary compounds, where Y_min ≤ 30%: “+++”; 30% < Y_min ≤ 50%: “++”. EC₅₀ ≤ 25 nM: “+++”; 25 nM < EC₅₀ ≤ 100 nM: “++”.

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.