Optimization of Diversity-Oriented Synthesis (DOS)-derived trypanocidal small molecule ML341 towards investigational new drug status for Chagas disease
Project Completed
Please click to see the final report.
  • Awarded Year
    2013
  • Awarded Amount
    $500,000
  • Disease
    NTDs Chagas disease
  • Intervention
    Drug
  • Development Stage
    Lead Identification
  • Collaboration Partners
    Eisai Co., Ltd., Broad Institute

Introduction and Background of the Project

Approximately 8 million people have Chagas disease, according to the most recent estimates. Chagas disease is endemic to Central and South America where there is a direct vector transmission of the parasite Trypanosoma cruzi that causes Chagas disease. The most impoverished people are disproportionately affected due to lack of clean living facilities, inability to spray for insect carriers of T. cruzi, and close proximity to infected animals and livestock. Benznidazole and Nifurtimox are the only currently approved drugs for Chagas disease.   Both drugs are only approved for the acute phase of the disease and both have extreme side effects. Currently, there are no approved drugs for treating the chronic phase of Chagas disease. New safe and efficacious drugs are critically needed to treat millions of people suffering from acute and chronic Chagas disease. Our efforts over the last 2 years have identified a new chemical series that show remarkable potency, selectivity and toxicity against T. cruzi. The goal of this proposal is to optimize this scaffold towards investigational new drug status for treating both chronic and acute stages of Chagas disease.

How can your partnership (project) address global health challenges?

The Center for the Science of Therapeutics at the Broad Institute in collaboration with biologists and physician-scientists in the Broad community, is undertaking therapeutics discovery projects aimed at testing therapeutic hypotheses in patients with small molecules.
We exploited novel Broad Institute’s compound collection to discover a small molecule-based anti-infective agent, with nanomolar cidal activity against the intracellular form of T. cruzi.


Eisai, headquartered in Tokyo, Japan, is determined to be proactive in improving access to medicines worldwide through partnerships with governments, international organizations, and other non-profit private sector organizations. Eisai is a signatory to the London Declaration, a coordinated effort to eliminate ten NTDs by 2020 through the largest global public-private partnership to date.


A common mission and complementary capabilities made the proposed collaboration between Broad and Eisai to further develop this lead series to a preclinical candidate ideal.

What sort of innovation are you bringing in your project?

Previous drug discovery efforts for Chagas disease have relied on a small number of chemotypes including nitro-heteroaromatics, azoles and vinyl sulfones that target nitroreductase, CYP51 and cruzain respectively. The small molecules explored in this project including ML341 are structurally unique and do not contain previously explored functionalities. We expect these small molecules will have unique biological mode of action.

Final Report

1. Project objective

 

A high‐throughput screening campaign of the Broad Institute’s Diversity Oriented Synthesis (DOS) collection of structurally and stereochemically diverse chiral molecules identified ML341 with inhibitory activity against the Tulahuen (TcVI) strain of Trypanosoma cruzi. The project objective was to perform lead optimization and determine the target mechanism of this unique molecule.

 

 

2. Project design

 

The program had three specific aims: 1) medicinal chemistry optimization to identify minimum pharmacophore, 2) optimization of in vitro ADME and in vivo pharmacodynamics, and 3) demonstration of in vivo efficacy with an optimized compound in a murine model of chronic Trypanosoma cruzi (T. cruzi).

 

 

3. Results, lessons learned

 

A phenotypic high throughput screen against recombinant Tulahuen strain of T. cruzi, the etiological agent of Chagas disease, with the Broad Institute’s Diversity-Oriented Synthesis (DOS) collection of unique structurally and stereochemically diverse collection of chiral molecules identified ML341 as a potent inhibitor of T. cruzi (ACS Med. Chem. Lett, 2014, 5,149-153).

 

Medicinal chemistry studies with the ML341 series focused on maintaining the potent inhibition against T. cruzi amastigotes (EC50 = 1 nM), reducing intrinsic clearance, and blocking undesired off-target inhibition of human CYP3A, a cytochrome P450 superfamily of genes that play a critical role in the metabolism of a variety of drugs. To understand the stereochemical and structural drivers of potency, the three stereocenters and the eight-member ring present in ML341 were systematically modified. These efforts ultimately yielded BRD2813, a 7-membered ring analog with only one chiral center having an EC50 of 32 nM against T. cruzi, PBS solubility of >100 µM, and intrinsic clearance of 29 mL/min/kg with human liver microsomes meeting the desired target product profile for Chagas lead molecule. BRD2813 and related potent analogs, for the most part, continued to inhibit human CYP3A. In collaboration with Prof. Kevin Read from University of Dundee, BRD2813 was subsequently shown to be an inhibitor of T. cruzi CYP51 (EC50 = 110 nM), a cytochrome P450 enzyme involved in T. cruzi ergosterol biosynthesis. Since a T. cruzi CYP51 inhibitor, posaconazole, previously failed to show a durable cure against Chagas disease in the clinic (N Engl J Med., 2014 370(20), 1899-908), further developmental efforts of this series was deprioritized.