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SCIENCE

Drugging the undruggable targets

  • SCIENCE

MODALITY

Cyrus therapeutics is primarily focused on developing small molecule medicines to conquer ‘undruggable’ cancer targets and expanding new chemical spaces such as targeted protein degraders (TPDs) and degrader-antibody conjugates (DACs). We are targeting difficult-to-drug proteins in multiple oncogenic pathways associated with RAS/MAP kinases, DNA damage response, cell cycle, and transcriptional & translational regulation, with an emphasis on synthetic lethal targets. 
1. Small molecule inhibition
Small molecule drugs typically aim to inhibit the functions of target proteins.
2. Targeted Protein Degradation
Targeted protein degradation (TPD) is a novel small molecule-based approach that induces the ubiquitination and subsequent degradation of a protein of interest (POI) by bringing an E3 ligase into close proximity with the POI. This process hijacks the E3 ligase and leverages the ubiquitin–proteasome system (UPS), the cell’s natural mechanism for disposing of unwanted proteins. There are two primary modalities for TPDs: the heterobifunctional degrader, known as PROTAC, and the monovalently behaving molecular glue degrader (MGD). TPDs operate in a catalytic manner, offering potential advantages over traditional small molecule inhibitors, in terms of modulating ‘undruggable’ targets, drug resistance, selectivity, and dosing. As an emerging modality for cancer treatment, TPDs hold the promise of not only expanding the druggable proteome beyond the reach of classical small molecule inhibitors but also enabling therapeutic strategies for targeting previously undruggable proteins. 1, 2
  • 1. Targeted protein degradation: current and future challenges, Hanz, A., Winter, G. E., Current Opinion in Chemical Biology, 2020, 56, 35-41.
  • 2. Targeted protein degradation: expanding the toolbox, Schapira, M., Calabrese, M. F., Bullock, A. N., Crews, C. M., Nature Reviews Drug Discovery, 2019, 18, 949–963.
3. Degrader-Antibody Conjugates
A Degrader-Antibody Conjugate (DAC), which combines a targeted protein degrader (TPD) with a monoclonal antibody (mAb), is an emerging concept representing the next generation of Antibody-Drug Conjugate (ADC) modalities.1 TPDs are expected not only to possess sufficient potency to serve as ADC payloads but also to enhance the safety profile of these highly potent therapies. This improvement stems from their catalytic mode of action and their additional selective targeting of cancer cells, whereas the selective cytotoxicity of current ADCs primarily depends on the expression of the target antigen. Consequently, this innovative convergence of two therapeutic approaches has the potential to address the urgent unmet needs associated with the payload-related toxicity and resistance of currently available ADCs. Furthermore, this new area is anticipated to lead future trends in ADC development, particularly in terms of payload diversification.
  • 1. Exploring the next generation of antibody-drug conjugates, Tsuchikama K., Anami Y., Ha SYY., Yamazaki CM., Nature Reviews Clinical Oncology, 2024, 21, 203-223.

TARGET

Cell Cycle & Transcriptional Regulation

Transcription factors (TFs) regulate gene expressions by binding to specific sequences such as promoters and enhancers. Large clusters of transcriptional enhancers are referred to as super-enhancers (SEs), which accelerate gene expression via occupying TFs and mediators. SEs play a critical role in gene expressions. Those are mainly associated with oncogenes to promote tumor cell survival and proliferation. SE-associated genes are more sensitive to the loss of master TFs than those found in conventional enhancers. Cyrus Therapeutics is developing novel inhibitors of TFs and their regulators that can block the activity of these dysregulated SEs, resulting in powerful drugs with wide applicability.

RAS / MAP Kinase Signaling

The RAS/MAPK pathway is one of the most well-characterized signal transduction pathways in cancer biology. This pathway transduces signals from the extracellular environment to the cell nucleus resulting in the induction of specific genes which control cell growth, proliferation, and differentiation. Abnormal activation of this signaling pathway by a series of alterations in the cellular genome drives oncogenesis in many human cancers including colon, pancreatic, and lung cancers. Unfortunately, drug resistance of RAS/MAPK inhibitors frequently arises from on-target mutations and signaling reactivations by feedback loop or target bypass. To overcome this resistance, Cyrus Therapeutics is developing a new targeted therapy for the RAS/MAPK pathway using small molecules, which can be used in both monotherapy and combination treatment with existing RAS/MAPK pathway-targeted inhibitors.

Synthetic Lethality

Cancer is a genetic disease and most cancers have signature mutations which drive development of cancers. Recent advances in Next Generation Sequencing (NGS) and Artificial Intelligence (AI) technologies provide higher resolution of the DNA maps of cancer cells and contribute to the development of patient-specific cancer therapies. Synthetic lethality is a concept of co-occurrence of mutations in two genes that induces cell death. This mechanism has been applied to develop new targeted therapy for cancer patients with BRCA1/2 mutations and selectively kills cancer cells with the mutations. The success of synthetic lethality-based therapy (e.g. PARP inhibitors) opened new therapeutic windows for genetic alterations associated with DNA damage response and cell cycle. Cyrus Therapeutics is using the results from NGS and AI to identify and target synthetic lethal genes and proteins. The development of new synthetic lethal-based therapies will precisely target cancer cells, improving outcomes and quality of life in cancer patients.

Cancer Immunotherapy

Cancer immunotherapy is a therapy that uses the body’s own immune system to kill cancer. The recent success of immunotherapies such as immune checkpoint inhibitors and CAR T-cells has initiated a paradigm shift in clinical and preclinical investigations. However, only a fraction of patients currently respond to immunotherapy, due to a highly immunosuppressive tumor microenvironment. Cyrus Therapeutics is developing small molecules that can reduce immune suppression in tumors and enhance activation of the immune anti-tumor killing abilities. These drugs can be used as monotherapy or combined with other cancer therapies to increase and broaden their efficacy.



PIPELINE

PUBLICATION & PRESENTATION