Pipeline Overview

Chitinase Inhibitors

Molecure has developed a unique series of chitinase inhibitors that modulate macrophage function, reducing the severity of inflammation and thus offering a novel therapeutic approach in inflammatory and fibrotic diseases. Elevated levels of one of the chitinases, chitotriosidase (CHIT1), are associated with inflammatory and fibrotic diseases, leading to excessive macrophage activation.

OATD-01

OATD-01, the lead drug candidate developed by Molecure, is a first-in-class dual chitinase inhibitor for the treatment of fibrotic and inflammatory diseases, including interstitial lung diseases such as sarcoidosis and idiopathic pulmonary fibrosis (IPF). OATD-01 is an innovative, effective and safe non-steroidal new chemical entity (NCE) – inhibitor of CHIT1 with a mechanism of action that targets inflammation and fibrosis simultaneously.

Numerous clinical studies and Molecure’s own translational data have shown that CHIT1 is upregulated in many inflammatory and fibrotic diseases, where its activity correlates with disease stage, progression and clinical prognosis. CHIT1 is most highly expressed in pathologically activated macrophages located in lesional areas.

Molecure studies showed that CHIT1 activity was significantly elevated in the serum of sarcoidosis patients and that CHIT1 expression was restricted to granulomas and localised in macrophages. Ex vivo OATD-01 inhibited the production of pro-inflammatory mediators in lung macrophages.

OATD-01 has demonstrated potent anti-inflammatory and anti-fibrotic effects in preclinical studies in various disease models, including sarcoidosis, MASH (metabolic dysfunction-associated steatohepatitis) and pulmonary fibrosis. In acute models of granulomatous inflammation in mice, OATD-01 showed anti-inflammatory effects. Furthermore, in a chronic model, inhibition of CHIT1 by OATD-01 led to a reduction in the number of organised granulomas in the lung and a decrease in sarcoidosis-related gene expression.

The Phase I clinical trials of OATD-01, which assessed the safety, tolerability, and pharmacokinetics of OATD-01 in healthy volunteers, were successfully completed in 2022. In March 2024, a Phase II clinical trial (KITE) was launched. It is a randomized, double-blind, placebo-controlled, multicenter study aimed at evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of OATD-01 in patients with active pulmonary sarcoidosis (more information available at https://thekitestudy.com/ and in Patients section.

Our second generation CHIT1 inhibitor program

Molecure has developed other selective CHIT1 inhibitors, structurally different from OATD-01, whose further development depends on the progress of OATD-01 clinical trials.

Arginase Inhibitors

Our proprietary candidate, OATD-02 is the first and only dual acting, highly potent arginase 1 and 2 (ARG1/2) inhibitor in cancer development, involved in tumor immunity via tumor metabolism regulation. 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 currently in Phase I clinical trials.

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 and intracellular metabolic changes.

OATD-02 restores effective antitumor immune responses by inhibition of arginases ARG1 and ARG2 subsequently increasing levels of arginine to promote the antitumor response. The ongoing Phase I clinical trial of OATD-02 is an open-label, multi-center, dose-escalation study aimed at evaluating the safety, tolerability, preliminary anti-cancer activity, and determining the maximum tolerated dose in patients with advanced or metastatic solid tumors. More information can be found in the Patients section.

Deubiquitinase Platform

At Molecure DUB proteins (deubiquitinating enzymes) 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 (ubiquitine-specific proteases, USPs), enzymes involved in the cleaving ubiquitin residues from 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 – suspended

Molecure is developing inhibitors of selective inhibitors 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 not only the level of proteins crucial for cancer cell proliferation, but also the 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 an advanced lead molecule, a selective USP7 inhibitor, that demonstrates safety and efficacy in several preclinical cancer models, including solid tumor models and hematologic malignancies. The USP7 inhibitor program has been suspended at the stage of characterization of the preclinical candidate.

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 lead optimisation stage and focuses on improving compounds’ pharmacological and pharmacokinetic profile.