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Disease Intervention Technology Lab

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Our mission
Our mission is to develop innovative technologies that selectively target biochemical networks to systematically understand and intervene in human diseases, using a multidisciplinary “team science” approach.

What we do
The Disease Intervention Technology Laboratory (DITL) is positioned to play a unique horizontal role within the disease research, translation and commercialisation landscape in Singapore and globally. Singapore has significant strengths in Use Inspired Basic Research (UIBR) through A*STAR, the Universities and other research institutions, and is primed for late-stage commercialisation activities through the Diagnostics Development Hub (DxD) or Experimental Drug Discovery Centre (EDDC).

DITL bridges between basic research and its commercialisation by implementing innovative technologies for the discovery, validation and enablement of novel molecular targets for next-generation disease therapeutics and diagnostics.

How we do it
We develop new technologies that harness protein engineering, chemistry, structure determination and chemical biology to overcome major challenges for therapeutics & diagnostics development.

We deploy our technology platforms for discovering & validating new targets using new genetic tools; creating chemical starting points for lead discovery (including small molecules, macrocycles or peptides) through structure-guided approaches; and enabling new classes of therapeutic or diagnostic targets via chemical biology.

We undertake basic research on cancer as a use-case to advance our systematic understanding of disease biology, empowering us to build, test and use our new technologies for therapeutics & diagnostics development.

We collaborate with other researchers in A*STAR, the Universities, and other institutions, as well as with industrial partners for technology development as well as therapeutics & diagnostics development. If you are interested in collaborating with us, please reach out to our assistant manager Raj Kaur at the following email: Rajindar_Kaur@imcb.a-star.edu.sg

DITL operates as a “team science” collective in which teams led by senior researchers with expertise in different fields work together to solve major scientific problems using multi-disciplinary approaches. Our research teams are led by Ashok Venkitaraman, Farid Gadhessy, Chris Brown and Zak Gates. Sir David Lane is an honorary member of DITL.

Members of our research team are here.

For an overview of the background knowledge and skill sets of our team members, please click here for publications since 2017. Research articles published prior to the formation of DITL have been included to highlight the scientific contributions of our laboratory members and the strength of our team.

Latest happenings
Ashok Venkitaraman is a scientific trailblazer
An interview with the DITL director, Ashok Venkitaraman by Jill Arul from Asian Scientist – an award-winning science and technology magazine that highlights R&D news stories. Please click on the link below for Prof Ashok’s insightful comments and vision for scientific advances within DITL and Singapore.
Asia’s Scientific Trailblazers: Ashok Venkitaraman - Asian Scientist Magazine.

2021 A*STAR Career Development Fund (CDF) recipients  
Congratulations to Yuri Frosi and David Koschut, who were awarded 2021 A*STAR Career Development Fund (CDF) in the latest competition, in which 64 awardees were chosen from over 300 eligible applicants. With this honour, Yuri and David join Teresa Ho who is an A*STAR Scholar as well as a current Career Development Award (CDA) and Young Individual Research Grant (YIRG) recipient within DITL.  

Features highlighting our team members, related topics or research
A Novel Discovery Platform to Identify First-in-Class Druggable Targets for Human Diseases
Reversing Cancer-Causing Faults in the Breast Cancer Gene BRCA2
Novel First-in-Class Drug Discovery Approach is Breaking New Ground in Anti-Cancer Therapeutics
USD 45M Series B Funding for UK-Based Biopharmaceutical Company’s Drug Discovery Programmes

Please feel free click on the links above to read or to download the DITL Latest Happenings here.
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Ashok VENKITARAMAN
Director
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David LANE
Honorary Fellow
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Farid GHADESSY
Principal Investigator
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Christopher BROWN
Principal Investigator
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Zak GATES
Senior Research Fellow


Ashok VENKITARAMAN

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Ashok VENKITARAMAN
Director of the Disease Intervention Technology Laboratory (DITL)
Lab Location: Neuros #06-04/05 
Email: Ashok_Venkitaraman[at]imcb.a-star.edu.sg   
NUS Email: csidir[at]nus.edu.sg   Tel: 64070553
Assistant Manager at IMCB: Raj Kaur;
Rajindar_Kaur[at]imcb.a-star.edu.sg
Personal Assistant at NUS: Mona Ng; mona[at]nus.edu.sg

Prof Venkitaraman holds a joint appointment as distinguished professor at the NUS Yong Loo Lin School of Medicine, a member of the National University Health System and Director of the Cancer Science Institute of Singapore. His laboratory is recognized for discovering the biological functions of the inherited breast cancer gene, BRCA2, and developing new technologies for drug discovery that have led to serial spinouts including PhoreMost. 
 
Lay summary:  
Cancer will affect about 1 in 3 humans at some stage in our lives. But not everyone is equally at risk of developing cancer. Some of us will experience a higher risk, either because of exposure to cancer-causing substances like cigarette smoke, or because of faulty genes that we inherit. Our research seeks to understand what makes some people more susceptible to cancer than others, and to use this new knowledge to find transformative new ways to detect, treat and eventually prevent cancer.
 
Research Summary:
We aspire to understand the mechanisms underlying human cancer susceptibility, in order to find innovative means to diagnose, treat or prevent (‘intercept’) cancer early in its evolution. To this end, my laboratory operates in three closely inter-linked spheres. Our uniquely multi-disciplinary research bridges from bench to bedside, subtending a wide range of techniques from molecular cell biology to single-cell/single-molecule imaging to structural biology, biophysics and chemistry. The aim is to develop actionable insights from which novel therapeutics and diagnostic entities can emerge.
 
Fundamental research:
People who inherit mutations affecting the ‘breast cancer gene’ BRCA2 become highly susceptible to many different epithelial cancers. My lab was amongst the first to discover that BRCA2 suppresses cancer by guarding genome integrity. We have since elucidated essential roles of BRCA2 in genome maintenance through its functions in DNA repair by homologous recombination, in stabilizing stalled DNA replication forks, and in accurate chromosome segregation during mitosis. Our work has broken technological silos to enable scientific advances, by combining structure determination by X-ray or cryo-EM, with somatic cell genetics and molecular cell biology, with biophysical approaches including advanced imaging. 

Use-inspired basic research (UIBR):
Our fundamental discoveries have provoked UIBR for translation to clinical impact. For example, we have discovered (combining innovative transgenic murine models & studies in patients) that cancer suppression by BRCA2 contravenes the classical Knudson ‘two-hit’ model, engendering new approaches for precision medicine now being applied in the clinic. We have identified new functions of the mitotic kinases PLK1 and AURKA, and their role in cancer drug resistance, now being targeted by pharma. We have recently discovered a novel cellular mechanism that links a ubiquitous class of environmental and endogenous substances – the aldehydes – with genome instability, opening new avenues for cancer therapy as well as prevention.

Technology development & commercialization:
To translate our UIBR, we have developed 3 new technology platforms for commercialization. Allo-targeting – a new concept to selectively target important cellular enzymes via their regulatory interactions rather than catalytic sites – will reach validation in 2021 through FTIM clinical trials (with our Cambridge Uni spin-out, Sentinel Oncology). Protein-interference (Protein-i) – a novel technology to rapidly identify & validate new drug targets – was spun out by Cambridge Uni into PhoreMost, a rapidly growing company with major pharma deals. Hyper-dimensional imaging microscopy (HDIM) – a high-dimensional photophysical method for biochemical imaging developed with Alessandro Esposito – has yielded prototype instruments. Together, these 3 platforms promise to accelerate drug discovery for many human diseases including cancer.


David LANE

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David LANE
DITL Honorary Fellow

Location: Neuros #06-04/05  Email: DPLane[at]imcb.a-star.edu.sg   
Prof Sir David Lane has recently stepped down as the Director of the p53 Lab but continues to hold a position as an Honorary Fellow within DITL. 

This page will be updated in the near future.


Farid GHADESSY

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Farid GHADESSY
DITL Principal Investigator

Lab Location: Neuros #6-04/05
Email: DPLane[at]imcb.a-star.edu.sg   Tel: 65869641
We are primarily interested in technology development with a view to generation of biologics (peptides and miniproteins) targeting dysfunctional signaling pathways. In particular, we develop and employ a range of directed evolution methodologies for protein engineering and selection. These approaches are also being used to engineer/re-purpose enzymes for industrially relevant applications, with current focus on development of “greener” enzyme alternatives for pharmaceutical synthesis. A further area of interest is development of novel biosensing platforms, with emphasis on modular protein biosensors for facile drug screening and diagnostic applications.


Charles JOHANNES

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Charles JOHANNES
DITL Principal Scientist

Lab Location: Neuros #06-04/05   
Email: charles_Johannes[at]imcb.a-star.edu.sg   Tel: 64070559

Dr. Johannes was trained as a synthetic organic chemist and received his Ph.D. in 1998 developing asymmetric catalytic carbon-carbon bond forming reactions and applying these methodologies to the total synthesis natural products. He started his career at EISAI a Japanese pharmaceutical company in Boston and also work for 2 start-up biotech companies (Infinity Pharmaceuticals and Forma Therapeutics).  Forma had several sites globally and Dr. Johannes moved to SG in 2008 as site Head and Director of chemistry and concurrently held an Adjunct Associate Professorship at Nanyang Technological Institute (NTU) in Singapore.  

From 2011-2019, Dr. Johannes served as a Principal Scientist and Head of Organic Chemistry (OC) Division at the Institute of Chemical & Engineering Sciences (ICES) managing a group of 35-50 and supporting broad range of research interests in catalytic technologies, synthesis of functional molecules and process research under SERC. During this time, Dr. Johannes held  various joint appointment roles at the Experimental Therapeutics Center (ETC) and the p53lab in BMRC.  In April 2019, he shifted to BMRC to re-visit his passion for the development of new therapeutics and related technologies as a Principal Scientist in the p53lab. 

Dr. Johannes managed the Peptide Engineering Programme (PEP) in A*STAR, was the theme PI in chemistry for the Cancer Immunotherapy Imaging (CITI) Program with Duke-NUS and is a Principal Investigator for Peptide collaborations with MSD and is a founder and President of the Peptide and Protein Society Singapore (P2S2). In April 2021, Dr. Johannes took up an appointment in the Disease Intervention Technology Lab (DITL) at IMCB where his current research focuses on therapeutic technology innovation. 

Through the development, discovery and application of peptide based technologies while using chemical-biology tools and probes for target validation the team explores new chemical space to make advances in disease intervention. These insights inspire the development of new therapeutic modalities and strategies for innovations in drug discovery including macromolecular delivery for intracellular targets.



Christopher BROWN

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Christopher BROWN
DITL Principal Investigator

Lab Location: Neuros #06-04/05  
Email: CJBrown[at]imcb.a-star.edu.sg   Tel: 64070559
The main focus of our team’s activities is to discover novel modalities such as macrocyclic peptides and mini-proteins in order to perturb intracellular biological interactions of therapeutic interest. In particular, we focus on targeting macromolecular surfaces that are considered to be intractable to small molecule binding.  

We use a variety of display technologies such as chemically modified phage and yeast libraries to efficiently search chemical and structural space to discover and isolate these molecules, which are then characterised using biophysical and structural methods. 

We are highly interested in developing techniques that extend the functionality of these molecules and allow these molecules to be delivered to their targets to enable target validation and therapeutic modelling studies. For example:

An attractive use of mini-proteins is that these modalities can be expressed in 3D cellular culture and animal systems to model the potential cellular effects of their interaction sites. If these molecules induce desirable phenotypes they can then be used as structural templates for therapeutic discovery programs.  

The fusion of miniproteins with protein domains of orthogonal functionality that can extend their use beyond conventional event driven modes of inhibition, such as E3 ligases, whereby multiple target molecules can be catalytically degraded by a single modality.


Zak GATES

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Zak GATES
DITL Senior Research Fellow 

Lab Location: Neuros #06-04/05  
Email: Zachary_Gates[at]imcb.a-star.edu.sg   Tel: 64074223
Our team is focused on the development of synthetic peptides as tools for accelerating therapeutic lead discovery. In this process, peptides function as a ‘stepping stone’ from therapeutic targets to small molecule drug leads, by facilitating the discovery and structural characterization of ‘ligandable’ sites on a target surface.

As a unique approach to ligand discovery, we build on recent advances in affinity selection – mass spectrometry, which facilitate the discovery of ligands from synthetic peptide libraries. We aim to develop this approach in three general directions:

• As a complimentary approach to in-vitro selection, for discovery of binding molecules (e.g., peptide macrocycles)
• To examine libraries containing a high proportion of non-proteogenic amino acids, and to engage ‘cryptic’ binding pockets (e.g. by covalent ‘tethering’)    
• To select for properties beyond binding affinity (e.g., passive membrane permeability)

We are also interested in using peptide ligands directly as tool compounds, in conjunction with emerging approaches for intracellular delivery. The ubiquitin proteasome system is an area of special interest.

Zak’s role within the DITL Team draws on his expertise with solid phase synthesis1, bioorganic chemistry2, and synthetic peptide libraries3-5. Our work is carried out collaboratively with the Institute of Chemical and Engineering Sciences, where Zak is jointly appointed.

Selected references:
1. Gates ZP, Dhayalan B, Kent SBH (2016) Obviation of hydrogen fluoride in Boc chemistry solid phase peptide synthesis of peptide-αthioesters. Chem Commun. 52(97):13979–13982
2. Dunkelmann DL, Hirata Y, Totaro KA, Cohen DT, Zhang C, Gates ZP, Pentelute BL (2018) Amide-forming chemical ligation via O-acyl hydroxamic acids. Proc Natl Acad Sci USA. 115(15):3752–3757
3. Gates ZP, Vinogradov AA, Quartararo AJ, Bandyopadhyay A, Choo Z, Evans ED, Halloran KH, Mijalis AJ, Mong SK, Simon MD, Standley EA, Styduhar ED, Tasker SZ, Touti F, Weber JM, Wilson JL, Jamison TF, Pentelute BL (2018) Xenoprotein engineering via synthetic libraries. Proc Natl Acad Sci USA. 115(23): E5298–E5306
4. Touti F, Gates ZP, Bandyopdhyay A, Lautrette G, Pentelute BL (2019) In-solution enrichment identifies peptide inhibitors of protein–protein interactions. Nat Chem Biol. 15(4): 410-418
5. Quartararo AJ, Gates ZP, Somsen BA, Hartrampf N, Ye X, Shimada A, Kajihara Y, Ottmann C, Pentelute BL (2020) Ultra-large chemical libraries for the discovery of high-affinity peptide binders. Nat Commun. 11:3183

A*STAR SCHOLARSHIP AWARD CEREMONY 2021

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