The 6th SKL Symposium on

CHEMICAL BIOLOGY& DRUG DISCOVERY

Date: 14-16 November 2019

Venue: Y817, Lee Shau Kee Building,The Hong Kong Polytechnic University

Chemical Biology & Drug Discovery化学生物学及药物研发国家重点实验室

On behalf of the Organizing Committee, I am delighted to

extend a warm welcome to all the delegates and guests for

joining us in the 6th State Key Laboratory Symposium on

Chemical Biology & Drug Discovery. This year, we are very

honored to have distinguished professors from Canada,

United States, Chinese Mainland and Hong Kong to join our

symposium. This symposium aims to gather scholars,

professionals and experts in the areas of chemical synthesis,

chemical biology and drug discovery that foster discussion

and possible collaboration. I hope new collaborations can be

built up after this symposium.

I would like to take this opportunity to thank all the speakers,

research personnel, students and administrative staff for their

support and contribution to this symposium. I wish you an

enjoyable and fruitful experience in PolyU and Hong Kong.

Thank you!

Professor Kwok-yin Wong

Director

State Key Laboratory of Chemical Biology & Drug Discovery

SKL Director’s Foreword

Day 1 14 November 2019

09:00-09:10 Opening remarks by Prof. Kwok-yin WONG

09:10-09:15 Photo-taking session

Morning session chair: Prof. Thomas Y. C. LEUNG

09:15-10:00 Prof. Dawei MA Page 6

10:00-10:45 Prof. Priscilla L. YANG Page 7

10:45-11:15 Coffee Break (30 minutes, Y8 Lift Lobby)

11:15-12:00 Prof. Kevin BURGESS Page 8

12:00-15:00 Lunch with invited speakers

Afternoon session chair: Dr. Man-Kin WONG

15:00-15:45 Prof. Ruben ABAGYAN Page 9

15:45-16:30 Prof. Larry M. C. CHOW Page 10

18:00-20:00 Dinner with invited speakers

Day 2 15 November 2019

Morning session chair: Dr. Cong MA

09:15-10:00 Prof. Shaomeng WANG Page 11

10:00-10:45 Prof. Xiaoguang LEI Page 12

10:45-11:15 Coffee Break (30 minutes, Y8 Lift Lobby)

11:15-12:00 Prof. Chao-Jun LI Page 13

12:00-12:05 Closing remarks by Dr. Cong MA

12:05-15:00 Lunch with invited speakers

18:00-20:00 Dinner with invited speakers

Day 3 16 November 2019

Session chair: Dr. Kin Fai CHAN

10:00-12:00 Laboratory Tour

Dawei MA

madw@mail.sioc.ac.cn

Associate Director and Professor

State Key Laboratory of Bio-organicand Natural Products Chemistry

Shanghai Institute of OrganicChemistry

Total Synthesis of Bioactive Alkaloids

In this lecture we report our recent efforts toward the total synthesis of alkaloids

by developing new synthetic strategies, which include a short and convergent

route for assembling gelsedine alkaloids and Et-743, total syntheses zaitine and

navirine C by using a chelation-triggered conjugate addition to a,b-unsaturated

nitrile and oxidative-dearomatization/Diels-Alder cycloaddition as the key steps;

and total synthesis of three kopsia alkaloids that featured an asymmetric

organocatalytic Michael addition to install one of their quaternary carbon centers

and an unprecedented Mn(III)-mediated oxidative cyclization to create the caged

ring system. These target molecules have very important biological activities,

which include pain-releasing & anti-inflammatory activities that displayed by

gelsedine alkaloids, antitumor activity showed by Et-743, and anti-leishmanial

activity performed by azitine. Our efficient synthesis will facilitate the chemical

biology studies of these natural products to reveal their action-modes.

Priscilla L. YANG

priscilla_yang@hms.harvard.edu

Associate Professor of Microbiology

Department of Microbiology

Harvard Medical School

Chemical Biology Approaches to the Discovery and

Validation of New Antiviral Targets and Strategies

Despite the successes of antiviral therapies for HIV and HCV, the number

of validated antiviral targets is quite small and combination therapy

remains the only effective strategy for avoiding viral resistance against

these and other RNA viruses. Applying chemical biology approaches to

study dengue and hepatitis C viruses, we have discovered and validated

new antiviral targets that were previously considered “undruggable” and

developed small molecule-induced “degraders” of viral proteins as potent

antivirals that have superior resistance profiles when compared to

conventional inhibitors. This work has provided proof-of-concept for thedevelopment of new, first-in-class antivirals.

Kevin BURGESS

burgess@tamu.edu

Rachal Professor of Chemistry (endowed chair), Department of Chemistry

Texas A & M University

PO Box 30012, College Station, TX 77842-3012, USA

Degradation Of Important Oncology Targets Via PROTACs:

TrkC and CDK4/6

Proteolysis targeting chimeras (PROTACs) are bifunctional organic molecules; one

“hand” of their bifunctionality binds an E3 ligase, while the other grabs a target

protein. PROTACs will draw an E3 ligase and the protein target into proximity to

deliver ubiquitin to the target, if there is a synergistic binding between the two

proteins; that ubiquitinylation will cause degradation of the target protein in the

proteasome.

This seminar, describes PROTACs we have formed for three target proteins: TrkC

and CDK4/6. We will explain why these proteins are important, why degradation

(or inhibition) of CDK4/6 is desirable but insufficient for chemotherapy, and our

strategy to attempt to work around this.

E3 ligaseligand

pomalidomide

target proteinligand

CDKs or TrkC

Ruben ABAGYAN

ruben@ucsd.edu

Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences

University of California San Diego

CA 92093, USA

Aiming at new targets in cancer or infectious diseases

Small molecule drugs have a substantial multi-target pharmacology that is under-

discovered, under-annotated, and essential for precision medicine. The drug-

target interaction networks of drugs (e.g.[1]) can be a starting point for drug

repurposing by projecting human proteomes to the proteins of infectious

pathogens. New targets of existing drugs, discovered by modeling, docking and

experiments, enable repurposing for new indications (e.g. medulloblastoma with

active Hedgehog pathway [2]). By aiming at different conserved locations we

found Hepatitis C NS3 inhibitors that hit both wild type and mutant forms [3].

Protein-protein interface between CK2a and b subunits critical in several cancers

can also be targeted with “fumigation” strategy [4]. The large PPI interfaces can

also be targeted with macrocycles [5]. Finally, new pathogens can be targeted by

building homology models of critical targets, followed by a docking selection and

experiment [6]. The multi-target pharmacology may also help to reveal and

control the dangerous adverse effects of some drugs using the FDA data (eg [7]).

References.1. Shi et al. Extended Multi-target Pharmacology of Anticancer Drugs. J Chem Inf

Model. 2019 Jun 24;59(6):3006-3017

2. Chalal et al. Nilotinib, an approved leukemia drug, inhibits smoothened signaling in

Hedgehog-dependent medulloblastoma. PLoS One. 2019 Sep 20

3. Meewan et al. Discovery of New Inhibitors of Hepatitis C Virus NS3/4A Protease

and Its D168A Mutant, ACS Omega, 2019, 4, 16999−17008

4. Kufareva, Bestgen et al. Discovery of holoenzyme-disrupting chemicals as

substrate-selective CK2 inhibitors. NatPG: Sci.Rep., 2019, Oct

5. Lam et al. Macrocycle modeling in ICM: benchmarking and evaluation in D3R

Grand Challenge 4. J Comput Aided Mol Des. 2019 Oct 9.

6. Shi et al. Identification of Four Amoebicidal Nontoxic Compounds by a Docking

Screen of Naegleria fowleri Sterol Δ8-Δ7-Isomerase and Phenotypic Assays. ACS

Infect Dis. 2019 Oct 17

7. Makunts et al. Analysis of postmarketing safety data for proton-pump inhibitors

reveals increased propensity for renal injury.. NatPG: Sci.Rep., 2019, 9(1):2282.

Larry M. C. CHOW

larry.chow@polyu.edu.hk

Professor

Department of Applied Biology and Chemical

Technology

The Hong Kong Polytechnic University

Modulation of ATP Binding Cassette (ABC) Transporters by

Synthetic Flavonoids: Application in Cancer Therapeutics

ATP-binding cassette transporters are involved in different pathological and

physiological functions. They contain highly conserved ATP-binding domains and

the transmembrane domains for substrate binding. We have developed a panel

of potent and selective modulators towards different ABC transporters, by

targeting their pseudo dimeric structure. We have applied these synthetic

flavonoids in different applications.

(1) Reversing cancer drug resistance: ABCB1 (P-glycoprotein), together with

ABCC1 and ABCG2, can mediate active efflux of cancer drugs. Our synthetic

flavonoid dimer FD18 and FD 15_8 can inhibit drug efflux mediated by ABCB1

and ABCG2 respectively, thereby reversing the drug resistance in cancer.

(2) Increasing oral bioavailability of cancer drugs: many cancer drugs e.g.

paclitaxel, are substrates of ABCB1 found on the apical side of the gut epithelial

cells and are, therefore, not orally bioavailable. Synthetic flavonoid FM04, when

co-administered orally with paclitaxel, can increase their oral bioavailability to

therapeutic level. Paclitaxel can now be used orally to reduce the side effects

associated with intravenous route of administration.

(3) Increasing brain penetration of cancer drugs: many cancer drugs, e.g.

tyrosine kinase inhibitors like sorafenib, are substrates of both ABCB1 and ABCG2

found in the apical side of the endothelial cell in the blood brain barrier (BBB),

resulting in a low brain penetration and therefore are ineffective towards

glioblastoma. We have developed a dual selective inhibitor of ABCB1 and ABCG2

(flavonoid dimer FD 12_9) and demonstrated that it can inhibit the ABCB1- and

ABCG2-mediated efflux in the BBB, restoring sorafenib to therapeutic level in the

brain. This is particularly useful in targeting temozolomide-resistant glioblastoma

which is one of the major causes of low survival rate in glioblastoma patients.

Targeting Gene Transcriptional Factors by PROTAC for the

Discovery of New Therapeutics

Gene transcriptional factors are considered as attractive therapeutic targets but

many of them are difficult to target. In the present lecture, I will present our

recent research in the discovery and development of PROTAC small-molecule

degraders, against proteins such as MDM2 protein, which regulates the activity

of transcriptional factor p53, BET proteins, which are histone reader proteins,

androgen and estrogen receptors and more recently STAT3, which has been

considered to be undruggable. Our studies demonstrate that PROTAC small-

molecule degraders are powerful chemical biology tools to study the functions of

these proteins and have the potential to be developed as completely new classes

of therapeutics.

Shaomeng WANG, PHD

shaomeng@umich.edu

Warner-Lambert/Parke-Davis Professor in Medicine; Professor of Medicine, Pharmacology and Medicinal Chemistry, Department of Pharmacology, University of Michigan, Ann Arbor, Michigan, USA

Natural Product Synthesis as a Driving Force to Address the

Antibiotic Resistance Crisis

Natural products and their derivatives have long been used as medicinal agents,

and they still make up a significant fraction of clinically approved drugs. Natural

product total synthesis provides a rich and unparalleled opportunity to develop

new synthetic transformations, conceive novel and general strategies to access

complex structures, and study the mechanism of action of bioactive targets. The

combination of the tools and principles of chemistry, together with the tools of

modern biology, allows us to create complex synthetic and natural molecules,

comprising processes with novel biological, chemical and physical properties.

This lecture will illustrate the opportunities that lie at this interface between

synthetic organic chemistry, chemical biology as well as drug discovery

endeavors by describing a series of examples that we are actively working on in

our laboratory. Through total synthesis applying the state-of-the-art new

synthetic strategies such as sequential C-H functionalizations, we are identifying

a number of new natural product-derived antibiotics targeting tuberculosis or

Gram-negative bacteria, which directly or indirectly block drug resistance with

novel mode of actions. Such molecules, are applied in combination with first

generation antibiotics to overcome resistance and rescue the activity of our

current antibiotic arsenal.

Xiaoguang LEI

xglei@pku.edu.cn

Professor

Department of Chemical Biology

College of Chemistry and MolecularEngineering

Center for Life Science

Peking University

Umpolung of Carbonyls as Organometallic Reagent

Surrogates

The organometallic reagents (R-M-X) from organic halides (R-X) plays the

central role in modern chemical synthesis. Prominent examples include

the nucleophilic addition to carbonyl compounds (represented by the 1912

Nobel Prize in Chemistry), the nucleophilic conjugate additions of

organocopper reagents, and various transition-metal mediated and

catalyzed cross-coupling reactions with aryl halides (represented by the

2010 Nobel Prize in Chemistry). In spite of the enormous success of

classical organometallic reagents, several limitations are intrinsically

associated with their generation and applications: a) non-natural organic

halides as feedstock; b) stoichiometric active metals as mediators; and c)

the lack of tolerance towards water and various common functional groups

in naturally occurring compounds. All these features will lead to extra

synthetic steps in chemical synthesis and generations of metal, halides,

and solvents wastes, increasing cost and lowering efficiency to convert

biomasses.

In this talk, we developed umpolung carbonyls as widely applicable

surrogates for classical organometallic reagents derived from organic

halides. Contrary to the classical organometallic reagents, such new

organometallic-reagent-surrogates exhibit some distinctive features: using

a catalytic amount of metal, circumventing organic halides as feedstocks,

and having great water and functional-group tolerance.

Chao-Jun LI

cj.li@mcgill.ca

Director, NSERC Create Center for Green Chemistry Training; E.B. Eddy Chair Professor of Chemistry and Canada Research Chair (Tier I)

Department of Chemistry, McGill University

Montreal, Canada

Note Page

Note Page

Address: State Key Laboratory of Chemical Biology and Drug Disvovery,

Department of Applied Biology & Chemical Technology,

The Hong Kong Polytechnic University, Hung Hom,

Kowloon, Hong Kong

Tel: (852) 3400 8686

Email: kwok-yin.wong@polyu.edu.hk

Fax: (852) 2364 9932

Website: https://www.polyu.edu.hk/abct/en/research/research_centres/skl/abo

ut_us/index.html