Drug Targets - Sciencesation

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23 Οκτ 2013 (πριν από 3 χρόνια και 10 μήνες)

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Новая парадигма разработки лекарств:
как мы и хотели это делать в 1999 году

Виталий
Пруцкий
,
Глава по информационному
обеспечению R&D, «
АстраЗенека

Россия»

Диалектика
-

или назад в будущее

What prompted the topic?


With DeCode Deal, Amgen Aims To Discover Drugs




Like We Meant To In 1999


http://www.forbes.com/sites/matthewherper/2012/12/10/with
-
decode
-
deal
-
amgen
-
aims
-
to
-
discover
-
drugs
-
like
-
we
-
meant
-
to
-
1999/


“It certainly wasn’t the deal
Amgen

investors were expecting from their new
executive team: This morning, the Thousand Oaks, Calif., biotechnology giant
dropped
$415 million
on
DeCode

Genetics, a genomics firm that Wall
Streeters

associate with the hype
-
filled days of the 2000s genomics boom and
a company they probably hadn’t thought about since it went bankrupt in
2010.”

Brief History of
DeCode

1996

Founded

1997

Drug
discovery
collaboration
with
Roche
-

$200M

2000

IPO
-

raised $173M

Price
>
$25

/
share

Market cap =
$1.2B

2009

Price
$0.23
/share

Assets


$69M

Liabilities
-

$313M

Chapter
11

2010

Re
-
launched

as
private;

$14M
invested

Dec 2012

Acquired by

Amgen for

$415M
in cash



Genotyped about 140,000 volunteers


nearly half of the Iceland's inhabitants



Sequenced the genomes of about 2,600 of these



Created a database of



Health / phenotypic records for the last 100 years, and



Genealogical records for ~1000 years

Has had considerable success in identifying genetic markers
associated with complex disease
"Decode Genetics will provide Amgen with an industry
-
leading ability to
identify and validate disease targets
in human populations. This will
enable Amgen to focus resources on programs that reach
the right human
disease targets
, thus avoiding investments in programs based on less well
-
validated targets
.“

http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1765710

Drug Targets and Target Discovery in





Drug Discovery Process

Target is where
usually




a good drug begins:



Relevant



Selective



Druggable


Drug Targets


How many are there?

1997


Drews

&
Reiser
:

483

drug targets

Drews
, J. &
Ryser
, S.

Classic drug targets.

Nature
Biotechnol
.

15
, 1318

1319 (1997)

2002


Hopkins&Groom
:

120


drug targets (rule
-
of
-
five compliant drugs only)

Hopkins, A. L. & Groom, C. R.

The
druggable

genome.

Nature Rev. Drug
Discov
.

1
, 727

730 (2002)

2003



Golden:


273

(protein) targets for approved then drugs

Golden, J. B.

Prioritizing the human genome: knowledge management for drug discovery.

Curr
.
Opin
. Drug
Discov
. Dev.

6
, 310

316 (2003)

2006



Wishart
:


14000

(6000) targets for all approved and experimental drugs

Wishart
, D. S.

et al
.

DrugBank
: a comprehensive resource for

in
silico

drug discovery and exploration.

Nucleic Acids Res.

43
, D668

D672 (2006)

2006



Imming
:


218

molecular targets for approved drug substances

Imming
, P., Sinning, C. & Meyer, A.

Drugs, their targets and the nature and number of drug targets.

Nature Rev. Drug
Discov
.

5
, 821

834 (2006)

2006



Zheng
:


268

'successful' targets in the Therapeutic Targets Database

Zheng
, C., Han, L., Yap, C. W.,
Xie
, B. & Chen, Y.

Progress and problems in the exploration of therapeutic targets.

Drug
Discov
. Today

11
, 412

420 (2006)

2006



Overington
:

324

drug targets for all classes of approved therapeutic drugs

(1,357 unique drugs: 1,204 'small
-
molecule drugs' and 166 'biological' drugs)

John P.
Overington
,
Bissan

Al
-
Lazikani

and Andrew L. Hopkins. How many drug targets are there?
Nature Rev. Drug
Discov
.

5
,

993
-
996

(December 2006)


Drug Targets


How many are there?

John P.
Overington
,
Bissan

Al
-
Lazikani

and Andrew L. Hopkins. How many drug targets are there?
Nature Rev. Drug
Discov
.

5
,

993
-

996

(December 2006)


NB
: Approximately
130

'privileged
druggable

domains' cover all current

drug
targets, compared to the projected number of protein families

(16,000) and
folds (10,000).

Drug Targets


slow rate of innovation

Of the 361 new molecular entities approved by the FDA between 1989
and 2000, only 6% targeted a previously
undrugged

protein domain

Between 198
3

and 2005:



The rate of new 'drugged' targets
-

5.3 per year



The rate of new protein families
-

1.9 per year

Drug Targets


what are they?

50% of drugs

60%
of

drug

targets

are

located

at

the

cell

surface
,
compared

with

only

22%
of

all

proteins

in

the

human

genome
.

Drug Targets


how many could be

there
?

Drug Target “has” to be “
druggable
”, i.e. have drug*
-
binding
domains
(*
Lipinski
rule
-
of
-
five compliant
orally bioavailable compounds
)

DRUG
-
CENTRIC VIEW:


~
3
000 (10
-
15%) proteins encoded by HG predicted as “
druggable
”.


Druggable

does not equal drug target:

Drug target “has” to be “disease related”, ideally disease
-
modifying

Drug Targets


how many could be there?

DISEASE
-
CENTRIC VIEW:

~1620
human protein sequences are linked directly to a disease (OMIM 2006)

~
7
-
10%

(1500
-
2000) of human genes are disease modifying

Druggability

HG = ~20000

Disease mod.

Drug Targets

600
-
1200

NB
: only ~50% of current targets would be classified as disease
-
related by OMIM

So, Why
DeCode
?



DeCode

is a Genetics Powerhouse



Access to genetic data, genealogies and medical records from 140000

Icelanders (population with strong founder effect).



Ability to find rare disease variants that can unmask
unrecognised


biological pathways containing new therapeutic targets.



Examples of
DeCode’s

recent work



Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits

Nature. 2013 May 23;497(7450):517
-
520. (http://www.ncbi.nlm.nih.gov/pubmed/23644456)

Rare nonsense mutation
within the
leucine
-
rich
-
repeat
-
containing G
-
protein
-
coupled receptor 4 (LGR4) gene
(c.376C>T) that is
strongly associated with low BMD, and with osteoporotic fractures.




Variant of TREM2 associated with the risk of Alzheimer's disease

N Engl J Med. 2013 Jan 10;368(2):107
-
116 (
http://www.ncbi.nlm.ni h.gov/pubmed/23150908
)

A rare
missense

mutation
(rs75932628
-
T) in the gene encoding the triggering receptor expressed on myeloid
cells 2 (
TREM2
), which was predicted to result in an R47H substitution, was found to confer a
significant risk of
Alzheimer's disease.




A mutation in APP protects against Alzheimer's disease and age
-
related cognitive decline

Nature. 2012
Aug

2;488(7409):96
-
99 (
http://www.ncbi.nlm.ni h.gov/pubmed/22801501
)

The strong
protective effect of the A673T substitution against Alzheimer's disease
provides proof of principle
for the hypothesis that reducing the β
-
cleavage of
APP

(
amyloid
-
β
precursor protein
) may protect against the
disease. (Supports the use beta
-
site APP cleaving enzyme 1 (BACE1) inhibitors in Alzheimer's therapy)

Why
Pharma
?

Genetics (when it works) may be the only ethical way to
discover and validate drug
targets relevant in human
disease

as opposed to relying on (animal) models

Example:

PCSK9

(
proprotein

convertase

subtilisin
/
kexin

type 9)


a new ideal of a drug target



PCSK9 degrades the receptors responsible for cellular uptake of low
-
density lipoprotein

cholesterol (LDL
-
c)



Mutations that turn up the volume on the gene result in high cholesterol and larger risk of heart

attacks; those that make it stop working lower cholesterol and lifetime cholesterol risk.



Elucidated by French researchers studying a family with a rare
autosomal

dominant form of

hypercholesterolemia (
Abifadel

et al. Mutations in
PCSK9

cause
autosomal

dominant

hypercholesterolemia.
Nat. Genet.

34, 154

156, 2003).




The idea is that genetics can start to prove a drug will work before there is

even a drug.

Why 1999 ?

Bayer's Millennium deal signals shift in R&D

$465 million
agreement … with Millennium Pharmaceuticals to discover
225

new drug targets

in
7
disease areas including osteoporosis and cancer.

Industry analysts think the deal signals Bayer's realization that the future lies with genomics
.


Nature Biotechnology 16, 1005 (
1998
)

(http://www.nature.com/nbt/journal/v16/n11/full/nbt1198_1005b.html)

What Now?

At present, genetics can offer only a partial and fragmented picture of
the biological processes underlying many diseases



Problems with scale (cohort size)



Problems with populations (mixed vs. homogeneous)



Problems with technologies (only now becoming cost
-
effective)



Problems with (analytical) methodologies



Problems with ethics.

“a substantial portion of missing heritability” may be overestimated and can
actually be explained by interactions among loci that have already been
identified…

Eric Lander, Broad Institute (
Proc.Natl.Acad.Sci
. USA

109, 1193

1198, 2012).

“The problem with that is nobody has been able to show
these interactions”

Kári

Stefánsson
, CEO and Founder of
DeCode

The Promise Remains:



to use genetic data to benefit patients

Back
-
up slides

Opportunities in Russia


population with
strong founder effect



BRCA1 inherited mutations are common in Russia and demonstrate very

pronounced founder effect.



A single BRCA1 allele, BRCA1 5382insC, may explain up to 4% of breast and

15% of
ovarian
cancer incidence.




BRCA1 hereditary lesions may also contribute to a substantial proportion of

“non
-
canonical” cancer types; for instance the 5382insC mutation is

detected in 4% of stomach cancers in Russia.




CHEK
-
2 mutations may be accountable for up to 4% of breast cancers in

Russia.




BRCA2 mutations are very rare in breast and ovarian cancers in Russia.

Drug Targets


slow rate of innovation

Of the 361 new molecular entities approved by the FDA between 1989
and 2000, only 6% targeted a previously
undrugged

protein domain

Between 1982 and 2005:



The rate of new 'drugged' targets
-

5.3 per year



The rate of new protein families
-

1.9 per year