Center For Integrative Chemical Biology & Drug Discovery
Center For Integrative Chemical Biology & Drug Discovery
Center For Integrative Chemical Biology & Drug Discovery
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
INNOVATION@Carolina<br />
A <strong>Chemical</strong> <strong>Biology</strong> Symposium<br />
“The hand is the cutting edge of the mind”<br />
http://www.pharmacy.unc.edu/labs/center-for-integrative-chemical-biology-and-drug-discovery
<strong>Drug</strong> <strong>Discovery</strong> – what we are trying to do at UNC<br />
Target selection –<br />
the disease connection<br />
hypothesis<br />
biology<br />
Small molecule tool<br />
to enhance target<br />
understanding & validation<br />
UNC can excel<br />
at small molecule<br />
driven elucidation of<br />
biology relevant to<br />
<strong>Drug</strong> <strong>Discovery</strong><br />
chemistry<br />
RESEARCH:<br />
hypothesis generation,<br />
revision & exploration at<br />
the chemistry/biology<br />
interface<br />
Efficacy<br />
in treating<br />
disease in<br />
Humans<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
<strong>Center</strong> for <strong>Integrative</strong> <strong>Chemical</strong><br />
<strong>Biology</strong> and <strong>Drug</strong> <strong>Discovery</strong><br />
Vision: The <strong>Center</strong> will be an<br />
innovative and sustainable scientific<br />
force in the creation of new small<br />
molecule therapeutics to improve<br />
public health, to transform the drug<br />
discovery paradigm and to place UNC<br />
at the forefront of translational<br />
medicine.<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
CENTER Capabilities<br />
• Assay Development (Bill<br />
Janzen)<br />
– 6 scientists<br />
– protein expression &<br />
purification<br />
– cell-based or in vitro assays<br />
– multiple platforms & readouts<br />
possible<br />
• Compound Screening<br />
– screens up to 100K<br />
compounds possible<br />
– Three HTS run since 4Q09<br />
– Small tube store installed and<br />
now loading<br />
• Medicinal Chemistry (Jian<br />
Jin & Xiaodong Wang)<br />
– 7 internal chemists<br />
– can support 3-5 projects<br />
– 4 external chemistry<br />
FTEs to support projects<br />
and tool compound<br />
synthesis<br />
• Computational Chemistry<br />
(Dmitri Kireev + postdoc)<br />
– design of focused<br />
screening sets, virtual<br />
screening<br />
– structure-based design<br />
– IT infrastructure<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
CENTER Mission<br />
Target Proposals<br />
from<br />
UNC Faculty<br />
“responsive<br />
collaborations”<br />
<strong>Center</strong><br />
Initiated<br />
Projects in<br />
<strong>Chemical</strong><br />
<strong>Biology</strong><br />
“prospective<br />
science”<br />
small molecule ‘probes’<br />
target validation<br />
drug leads<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
Envisioned process at UNC for<br />
responsive projects<br />
Target I.D.<br />
&<br />
Validation<br />
Investigator<br />
driven target<br />
proposals<br />
with validation<br />
data from<br />
HT-genomics,<br />
HT – siRNA,<br />
In vivo<br />
models<br />
1 year,<br />
50%<br />
success<br />
Hit I.D.<br />
Assay<br />
development<br />
MTS,<br />
focused<br />
sets,<br />
knowledge<br />
-based<br />
design,<br />
HTS<br />
1 year,<br />
80%<br />
Lead<br />
I.D.<br />
SAR dev.,<br />
compd<br />
optimiz.,<br />
Cellular -<br />
in vivo<br />
efficacy,<br />
initial<br />
dmpk,<br />
selectivity<br />
profiling,<br />
target<br />
validation<br />
2-3 yrs,<br />
50%<br />
Candidat<br />
e I.D.<br />
lead opt.,<br />
In vivo<br />
efficacy &<br />
safety,<br />
7 day tox.,<br />
scale-up,<br />
dmpk in<br />
3 species,<br />
target<br />
validation<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong><br />
6
How do faculty currently establish a<br />
collaboration with the CICBDD<br />
• Drop by & chat<br />
– Reviewed by <strong>Center</strong> Faculty<br />
• General Criteria:<br />
– Disease relevance of target/pathway<br />
– Potential scientific impact of small molecule tools<br />
– Tractability of assay development and ligand<br />
discovery<br />
– Portfolio balance and fit with center expertise<br />
– Funding status & prospects<br />
7<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
Portfolio Goals<br />
Stage<br />
Assay<br />
Developed<br />
Validated Hits<br />
Leads/probes<br />
2010<br />
Goals –<br />
projects that<br />
will complete<br />
the indicated<br />
stage during<br />
this year<br />
12<br />
Eppin<br />
GRK2/3<br />
CCR7<br />
RGS<br />
G9a<br />
SMYD3<br />
DNMT3b<br />
PAP<br />
ROR2<br />
LKB1<br />
A1<br />
IKKε<br />
9<br />
MBT – HTS & synthesis<br />
Eppin – HTS<br />
RGS – HTS<br />
SMYD3/SETD8 – HTS<br />
LKB1 – focused<br />
GRK2/3 – focused<br />
PAP – synthesis<br />
DNMT3b - synthesis<br />
4<br />
Mer kinase<br />
FS D2<br />
HMT<br />
Kinase lead<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong><br />
8
CENTER Mission<br />
Target Proposals<br />
from<br />
UNC Faculty<br />
“responsive<br />
collaborations”<br />
<strong>Center</strong><br />
Initiated<br />
Projects in<br />
<strong>Chemical</strong><br />
<strong>Biology</strong><br />
“prospective<br />
science”<br />
small molecule ‘probes’<br />
target validation<br />
drug leads<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
<strong>Chemical</strong> biology of<br />
chromatin regulation<br />
DNA<br />
methylation<br />
DNA<br />
Lysine<br />
Histone<br />
modification<br />
Histone<br />
GOAL = <strong>Chemical</strong> Probes<br />
Modification Write Read Erase<br />
Acetyl (Ac) HAT Bromo HDAC<br />
Methyl (Me n ) KMT Royal KDM<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
CICBDD Team<br />
<strong>Center</strong> <strong>For</strong> <strong>Integrative</strong> <strong>Chemical</strong> <strong>Biology</strong> & <strong>Drug</strong> <strong>Discovery</strong>
Change language