Pipeline Overview

Molecure discovers and develops breakthrough small molecule drugs that modulate novel RNA and unexplored protein targets 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 has allowed us to create a broad pipeline of drug candidates targeting unique and unexplored protein targets, as well as a small molecule mRNA targeting discovery platform.

CLINICAL CANDIDATE
SELECTION
Molecular
Target
Indications
Target Validation
Hit-To-Lead
Lead
Optimization
In Vivo Poc
Preclinical
Development
Regulatory Process
Phase I
Phase II
mRNA TARGETS
Undisclosed mRNA
In progress
INFLAMMATION/ONCOLOGY
PROTEIN TARGETS
OATD-01 CHIT1/AMCASE
Sarcoidosis, other ILDs
2ND GENERATION CHIT1
NASH, CNS, ILDs
INFLAMMATION
& FIBROSIS
UNDISCLOSED
Fibrosis
Under an Option to License Agreement from
OATD-02 ARG1/ARG2
ImmunoOncology
2ND GENERATION OATD-02
ImmunoOncology
YKL-40
ImmunoOncology
ONCOLOGY
USP7
ImmunoOncology
UNDISCLOSED USP
ImmunoOncology
Current Status
2022-23 Predictions

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 have the ability to bind a small molecules that at the same time are potential drug targets i.e. are linked to a disease. Human transcriptome (mRNA molecules coding those proteins) is underexploited as a new source of therapeutic targets and for long considered ‘undruggable’ via conventional approaches.

This bioinformatics platform gives Molecure the chance to outperform standard methods used in discovery of small molecule drugs targeting RNA.

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.

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 modeling 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.

Targeting unexplored proteins

We are discovering and developing first-in-class small molecules in oncology, inflammation and fibrosis that target/interact with selected, unexploited proteins.

We have already validated the strength of our discovery and translational capabilities by generating a diverse pipeline consisting of seven distinct programs, including:

  • 1 program in clinical development and Phase II ready with another molecule expected to enter the clinic in the second half of 2022
  • 5 programs in preclinical development, spanning and targeting 4 unchartered novel target families (arginases, chitinases, deubiquitinases and an undisclosed target).

Arginase Inhibitors

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 lead 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 expected to enter Phase I/II clinical trials in the second half of 2022.

In collaboration with our partner SyVento, we are also developing proprietary liposomal formulations of arginase inhibitors with the potential to increase their bioavailability and targeted exposure in the tumor.

Chitinase Inhibitors

Molecure has developed a unique array of chitinase inhibitors which modulate the function of macrophages, reducing exacerbated inflammation, and offering a new therapeutic approach to inflammatory and fibrotic disease. Elevated levels of one of the chitinases  – chitotriosidase (CHIT1) are associated with inflammatory and fibrotic diseases, leading to excessive activation of macrophages.

OATD-01

OATD-01, Molecure’s lead candidate, 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 inhibitor of CHIT1 and has demonstrated in preclinical studies to have potent anti-inflammatory and antifibrotic effects in various disease models, including lung fibrosis, NASH and sarcoidosis.

Phase 1 studies were completed in 2020 and a Phase II trial in patients with sarcoidosis is expected to start in 2023.

OATD-01 is an innovative, efficacious and safe, non-steroidal new chemical entity (NCE) – a dual inhibitor of AMCase and CHIT1 with a novel mechanism of action simultaneously targeting inflammation and fibrosis.

Multiple clinical studies in addition to Molecure’s own translational data have demonstrated that CHIT1 is overexpressed in multiple inflammatory and fibrotic diseases where its activity correlates with a disease stage, progression and clinical prognosis. CHIT1 is mostly expressed in pathologically activated macrophages localized to areas of pathology.

Molecure’s  research has shown that  CHIT1 activity was significantly upregulated in serum from sarcoidosis patients and that CHIT1 expression was restricted to granulomas and localized in macrophages. Ex vivo OATD-01 inhibited pro-inflammatory mediators’ production by lung macrophages .

In acute models of granulomatous inflammation in mice, OATD-01 showed anti-inflammatory effects. Further, in the chronic model inhibition of CHIT1, OATD-01 led to a decrease in the number of organized lung granulomas and the expression of sarcoidosis-associated genes.

Molecure has developed an oral, once-daily pill for improved ease of usage and patient compliance . Phase I was completed in 2020 and during 2021-2022 drug-drug interaction studies were completed by former partner Galapagos.

OATD-01 has a high therapeutic potential in diverse inflammatory and fibrotic diseases with high unmet medical needs such as sarcoidosis, but also idiopathic pulmonary fibrosis and NASH where efficacy was demonstrated in preclinical models. Possible further indications

In 2020, Molecure’s lead chitinase inhibitor, OATD-01 was  successfully out-licensed to Galapagos NV 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 continues with the development of OATD-01 and is looking to advance this asset into a Phase 2 clinical trial in 2023.

 

 

YKL-40 Program

This program has led to the discovery of OAT-3912 which strongly binds YKL-40. Preclinical colorectal cancer models demonstrate that OAT-3912 slows tumor growth via reactivation of immune response and offers potential therapeutic benefit in various types of cancer.

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.

Second generation CHIT1 inhibitor

CHIT1 is also involved in the development 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, for the treatment of these diseases, which have been chosen for proof-of-concept validation, namely non-alcoholic steatohepatitis (NASH) and neuroinflammatory indications.

Deubiquitinase (DUB) Inhibitor Program – USP7

Molecure is developing inhibitors of DUBs, including a selective inhibitor of ubiquitin specific protease 7 (USP7), whose high expression is seen to be aberrant in a number of tumor indications, promoting oncogenesis. USP7 regulates the levels of multiple proteins involved in the cell cycle and the immune response, particularly in the homeostasis of p53, a tumor suppressor protein and regulator of the cell cycle.

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 mode of action of USP7 inhibitor is based on stimulating the body’s immune response to cancer and via direct inhibition of cancer cell proliferation combined with apoptosis. The pharmacological profile of Molecure’s nominated clinical candidate will enable oral dosing in patients.

Ubiquitination, the addition of ubiquitin to a substrate, is a post translational modification critical to cell homeostasis. Expression of deubiquitinases or ubiquitin-specific proteases (DUBs/USPs), enzymes involved in the deubiquitination of proteins, can be abnormal in tumors and the tumor microenvironment, presenting DUBs as a potential important group of targets for anticancer therapeutic agents.

Publications

Inhibition of CHIT1 as a novel therapeutic approach in idiopathic pulmonary fibrosis

Development of Dual Chitinase Inhibitors as Potential New Treatment for Respiratory System Diseases

Benzoxazepine-Derived Selective, Orally Bioavailable Inhibitor of Human Acidic Mammalian Chitinase

Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma

Discovery and Pharmacokinetics of Sulfamides and Guanidines as Potent Human Arginase 1 Inhibitors

Posters

Discovery of small molecule compounds that modulate binding of YKL-40 with carbohydrates or galectin-3 as potential therapeutics for cancer I 37th ACS National Medicinal Chemistry Symposium, 26-29/06/2022 New York

Targeting Chi3l1 by a small molecule activates macrophages, June 15-17.2022, Lyon, France

Pharmacological inhibition of chitotriosidase (CHIT1) as a novel therapeutic approach for sarcoidosis I 12-16 June, 2022, Keystone, CO, USA

EFMC-ASMC’19 – September 1-5, 2019 | Athens, Greece

ACS National Meeting & Expo – August 25 – 29, 2019 | San Diego, CA

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