Molecure, a clinical stage biotechnology company, discovers and develops breakthrough small molecule drugs that modulate unexplored protein targets and novel RNA to treat cancer, fibrotic and inflammatory diseases.
Our exceptional in-house medicinal chemistry and biology capabilities, along with novel target insights gained from leading academic centers, have allowed us to create a broad pipeline of drug candidates targeting unique and unexplored protein targets. Our lead assets, OATD-01 and OATD-02, are in clinical development for the treatment of sarcoidosis and solid tumors respectively.
In addition, we are developing a unique RNA platform, to discover small molecule compounds that interact directly with the mRNA of disease-related proteins, with significant potential across multiple disease areas.
Unique RNA platform
Molecure is developing a unique RNA platform to discover small molecule compounds that interact directly with the mRNA of disease-related proteins. By modulating mRNA biological function and affecting its translation we are able to discover medicines with a novel mechanism of action.
This approach offers access to potentially thousands of new therapeutic targets, which were previously considered ‘undruggable’.
From the estimated ∼20 000 proteins that comprise the human proteome, only 15% are considered “druggable”. This is because just a fraction of proteins that are potential drug targets i.e. are linked to a disease, have the ability to bind a small molecules.
As a result, the human transcriptome (mRNA molecules coding those proteins) is underexploited as a new source of therapeutic targets and for long considered ‘undruggable’ via conventional approaches.
Molecule has developed a bioinformatics platform and positions it to outperform the standard methods used in discovery of small molecule drugs targeting RNA.
Molecure’s workflow consists of:
- Identifying unique, stable and functional motifs within mRNA of clinically relevant genes associated with disease-related functions and previously undruggable targets, using exclusive algorithms. Those predicted motifs are then confirmed at a single nucleotide resolution by NGS and chemical probing.
- Using a combination of AI and dynamic NMR assessment, focusing on those mRNA motifs with sufficient structural sophistication that make it likely that high affinity and specificity small molecule binding sites can be mapped out.
- Using a combination of virtual modelling and tradition medicinal chemistry, screening and refining hit and lead compounds and further assessment of their potency in vitro and in vivo to discover new drug-like molecules interacting with mRNA.
Molecure’s current aim is to provide the industry with an engine to identify hit compounds, demonstrating druggability of mRNA targets, which opens tremendous scientific and medical opportunities.
The development of Molecure’s mRNA platform is being supported by an exclusive research collaboration agreement with the International Institute of Molecular and Cell Biology (IIMCB) in Warsaw.
This collaboration provides the company with access to world-leading and unique bioinformatics tools developed by the Laboratory of Bioinformatics and Protein Engineering (LBIB) at IIMCB, headed by prof. Janusz Bujnicki.
Targeting unexplored proteins
Molecule is discovering and developing first-in-class small molecules in oncology, inflammation and fibrosis that target/interact with selected, unexplored proteins.
We have generated a diverse pipeline consisting of seven distinct programs, validating the strength of our discovery and translational capabilities, including:
- 1 program in clinical development and Phase II ready with another molecule entered the clinic in Q1 2023
- 5 programs in preclinical development, spanning 4 unchartered novel target families (arginases, chitinases, deubiquitinases as well as one undisclosed target).
OATD-01, Molecure’s lead candidate, is an oral, once-daily, first-in-class highly selective CHIT1 inhibitor for the treatment of sarcoidosis. CHIT1, or Chitotriosidase, is produced by pathologically activated macrophages, and is the primary active chitinase in the lung.
OATD-01 is potentially a disease modifying therapy that could transform the standard of care.
Multiple published studies, as well as Molecure’s own translational data has shown CHIT1, the target of OATD-01, to be upregulated in sarcoidosis and the level of upregulation to be correlated with disease severity. In sarcoidosis patients, the over-expression of CHIT1, is also a marker of disease progression.
Phase I studies have demonstrated OATD-01 to be safe and to have a novel therapeutic mechanism of action, simultaneously targeting inflammation and fibrosis.
Phase II studies with OATD-01 in sarcoidosis patients are expected to start in the second half of 2023.
Pharmacological Inhibition of Chitotriosidase (CHIT1) as a Novel Therapeutic Approach for Sarcoidosis
OATD-01 has demonstrated potent anti-inflammatory and antifibrotic effects in various disease models and has high therapeutic potential in diverse inflammatory and fibrotic diseases with high unmet medical needs such as sarcoidosis, as well as idiopathic pulmonary fibrosis and NASH where efficacy was demonstrated in preclinical models. Possible further respiratory indications include inflammatory asthma, COPD, other Interstitial Lung Diseases (scleroderma and rheumatoid arthritis-associated fibrosis) or in non-pulmonary diseases, diabetic nephropathy, ALS and Crohn’s disease.
OATD-01 was successfully out-licensed to Galapagos NV in 2020 for the global development and commercialization of the product. As a result of a portfolio review by Galapagos in 2022, Molecure regained full rights to OATD-01 together with all the related IP and know-how.
Molecure is now focused on developing OATD-01 to realise its significant clinical potential and is looking to advance this asset into a Phase 2 clinical trial in patients with sarcoidosis in 2023.
OATD-01 in Sarcoidosis/The relevance of Chitinase inhibitors in Sarcoidosis
Sarcoidosis is a systemic inflammatory disease that is characterized by the formation of small clumps of inflammatory cells, called granulomas in various organs, mainly the lungs and the lymphatic system. Its cause is unknown.
Sarcoidosis is a global disease, affecting both men and women with a prevalence of about 5–50 in 100 000, with 70% of the patients aged between 25 and 45 years.
The most severe and frequent complication of sarcoidosis is the occurrence of pulmonary fibrosis. This is usually associated with significant impairment of pulmonary function, whereby granulomatous inflammation leads to pulmonary fibrosis. The development of pulmonary fibrosis is associated with significant increase in morbidity and can be fatal.
There is currently no cure for sarcoidosis and existing treatments such as corticosteroids only modify/impede the development of granuloma formation and come with a significant range of side effects. There is also little evidence of extended therapeutic efficacy.
During preclinical development, OATD-01 has been shown to significantly decrease the disease severity, to suppress the development of granulomas and reduce inflammation in the lungs of treated animals.
Our second generation CHIT1 inhibitor program
CHIT1 is also involved in the pathology of various diseases with inflammatory and fibrotic components, including non-alcoholic steatohepatitis (NASH), and potentially a broad spectrum of neurological diseases that are characterized by excessive activation of inflammatory cells in the brain (neuroinflammation).
Molecure is developing other selective CHIT1 inhibitors, structurally different from OATD-01, which have been selected for proof-of-concept validation in models of these diseases.
Arginase 1 (ARG1) and Arginase 2 (ARG2) are validated targets that have been found on a variety of tumor types where their increased activity correlates with more advanced disease and worse clinical prognosis due to diminished arginine levels.
Our second proprietary candidate, OATD-02 is the first and only dual acting, highly potent arginase inhibitor in cancer development, involved in both tumor immunity and metabolism. It has been selected as a clinical candidate for the potential treatment of a broad range of tumors in combination with other anti-cancer therapeutics.
OATD-02 is on the stage of Phase I clinical trials.
At Molecure DUB proteins comprise a potential important group of targets for anticancer therapeutic agents. Ubiquitination, the addition of ubiquitin to a protein, is a post-translational modification affecting the lifespan of proteins and therefore, critical to cell homeostasis. Expression of ubiquitin-specific proteases (USPs), enzymes involved in the cleaving ubiquitin residues froms proteins, can be abnormal in tumors and the tumor microenvironment. This way cancer cells extend the life of specific proteins that allow them for uncontrolled growth.
USP7 Inhibitor Program
Molecure is developing inhibitors of selective and oral inhibitor of ubiquitin specific protease 7(USP7), whose high expression is seen to be aberrant in a number of tumor indications, promoting oncogenesis. In our studies, we have shown that in cancer USP7 regulates the level of many proteins involved in the immune response, hence inhibition of USP7 activity leads to the activation of T cells and the stimulation of the immune system to act against cancer cells.
Molecure has identified a lead molecule OAT-4828, a potent and selective USP7 inhibitor, which demonstrates safety and efficacy in selected models of cancer. The project is at the stage of searching a candidate for preclinical development.
USP21 Inhibitors Program
The USP21 inhibitor program is based on the experience built by Molecure and naturally expands the pool of therapeutic targets from the family of enzymes – ubiquitin-specific proteases (USP). The results obtained so far by Molecure’s scientists confirm that the lack of USP21 in cancer cells slows down their proliferation and migration, and also regulates the level of key proteins involved in oncogenesis, which have been considered “undruggable targets” for years. USP21 plays an important role in the modulation of cancer cell metabolism by affecting mitochondrial function. This project is currently at the hit-to-lead stage and focuses on optimizing the identified molecules in terms of their activity, selectivity and pharmacological profile.
A new project targeting an undisclosed signaling pathway crucial to the development of fibrosis
The project aims at the development of new small molecule inhibitors of an undisclosed signaling pathway with potential use in the treatment of fibrotic diseases, in particular idiopathic pulmonary fibrosis. The project is at the stage of lead optimization with an objective to improve lead molecule’s activity and pharmacological profile. The screening of compounds utilizes phenotypic assays and is based on the screening cascade developed by the Molecure team using the know-how from the University of Michigan (provided under a non-exclusive license agreement, including know-how in the area of discovering new molecules targeting an undisclosed signaling pathway crucial for the development lung fibrosis).
YKL-40 which belongs to the chitinase-like proteins (CLPs) family, is a secreted protein with homologies to chitinases but devoid of catalytic function. High levels of YKL-40 are linked to poor prognosis, progression and the severity of various inflammatory disorders and numerous types of cancer. The protein is produced and secreted by immune cells (especially macrophages, neutrophils) and various structural cells like fibroblasts, smooth muscle, epithelial, endothelial and also cancer cells.
The program led to the discovery of the compound OAT-3912, which binds strongly and selectively to YKL-40. In preclinical studies in a colorectal cancer model, OAT-3912 has been shown to slow tumor growth by reactivating the immune system response, offering potential therapeutic benefits in many types of cancer. The compound has also shown efficacy in preclinical models of inflammatory and fibrotic diseases.