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RFP Year2020
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Awarded Amount$210,936DiseaseMalariaInterventionDrugDevelopment StageHit IdentificationCollaboration PartnersTakeda Pharmaceutical Company Limited , Eisai Co., Ltd. , Daiichi Sankyo, Inc. , Medicines for Malaria Venture (MMV)
Introduction and Background of the Project
Introduction
This project is unique in that three Japanese pharmaceutical companies are collaborating with Medicines for Malaria Venture (MMV) and its partners, with funding from GHIT Fund, to screen Japanese compound libraries against novel, validated antimalarial biological targets.
Project objective
The objective is to complete screening of approximately 60,000 compounds (20,000 from each company) against two antimalarial targets Plasmodium falciparum CLK3 and Acetyl CoA synthetase, with the goal to deliver validated hits that will form the basis of (GHIT funded) Hit-to-Lead projects and ultimately new candidate drugs as potential treatments for malaria.
Project design
Eisai Co., Ltd. (Eisai), Takeda Pharmaceutical Co., Ltd. (Takeda) and Daiichi Sankyo Co., Ltd (Daiichi Sankyo) are each providing compounds from their respective company compound collections to MMV who will facilitate the screening of these libraries against two parasite biological targets.
How can your partnership (project) address global health challenges?
There is an urgent need for new medicines for malaria that overcome current and anticipated future resistance risks of drugs on the market or in clinical development. This project addresses this through a focus on two high value, biologically validated and novel antimalarial drug targets. As such candidate drugs delivered ultimately from this project are expected to overcome resistance from other antimalarials.
What sort of innovation are you bringing in your project?
This project and project framework brings two new innovations: first the focus on screening against discrete, novel, parasite biological targets with the intent of conducting target based drug discovery to candidate selection, and second, the logistical efficiency that arises from a willingness of three Japanese companies to contribute compound libraries for each of the two screens. This demonstrates exceptional leadership and collaboration on the part of the Japanese Pharma and a desire to contribute to MMV’s mission to discover, develop and deliver new antimalarials for the world.
Role and Responsibility of Each Partner
Eisai, Takeda and Daiichi Sankyo are each providing approximately 20,000 compounds which will be screened blind by MMV’s screening partners. MMV and each Japanese company will then confirm the hits and evaluate the potential for new Hit-to-Lead projects.
Final Report
1. Project objective
The project's first objective was the high throughput screening (HTS) of three Japanese Pharma libraries against two biological targets (Pf AcCS and Pf CLK3). Following completion of the high throughput screen, the second objective was re-testing fresh samples of selected compounds (including analogues if available) and then further profiling in the assays described in the MMV Active Confirmation cascade (Pf 3D7, Pf Dd2, HepG2, Albumax binding, LogD, kinetic solubility, human liver microsomes and rat hepatocytes). Compelling novel compounds meeting the MMV Confirmed Active criteria will form the basis of a new GHIT HTLP proposal.
2. Project design
Daiichi-Sankyo, Eisai and Takeda provided approximately 20,000 compounds per company for screening against Pf AcCS and Pf CLK3 and their human orthologues. The compounds were supplied structure-blinded. The Pf AcCS assay was carried out at the University of Dundee (UK) and the Pf CLK3 assay at BioAscent (UK) using protein provided by Prof Andrew Tobin (Uni. Glasgow, UK). Active confirmation was carried out at TCGLS (India).
3. Results, lessons learned
12 compounds from the Takeda library, 51 compounds from the Daiichi Sankyo library and 25 compounds from the Eisai library were identified with PfACS pIC50 > 5 and HuACS pIC50 < 4. 2 Takeda, and 13 Daiichi Sankyo were tested in active confirmation. However, none of them will be progressed. The compounds are weakly active (3D7 IC50 > 10 µM) and not highly compelling start points for an HTLP. Eisai has selected 10 compounds to be resynthesized for active confirmation (to be completed post-term).
33 compounds from the Takeda library, 88 compounds from the Daiichi Sankyo library and 153 compounds from the Eisai library were identified with PfCLK3 pIC50 > 5. 4 Takeda compounds (all commercially available) and 9 resynthesized Daiichi Sankyo compounds were tested in active confirmation. However, none of them has good potency (i.e. pIC50 > 5) on both PfCLK3 biochemical assay and asexual blood stage assay. Eisai has selected 10 compounds to be resynthesized for active confirmation (to be completed post-term).
Compelling novel compounds meeting the MMV Confirmed Active criteria from either HTS campaign will form the basis of a new GHIT HTLP proposal.
There are several learnings from this project. The design of the project (multiple partners, multiple targets and multiple test centres) had the potential to be an efficient use of time and resources. However, the assays must be ‘screen ready’ and all consumables (e.g. protein are available) before the start of the project. Unfortunately, this was not the case for the Pf CLK assay. Secondly, testing compounds from multiple partners can be problematic when timelines (e.g. resupply of compounds for DRC) are different for different partners, and the assays need to either be run individually (at increased cost) or delayed until all samples are on-site.
In the future, a simpler project design is recommended for when validated HTS-ready assays.
Investment
Details
Screening Program