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Candidate
Knowledge
Info
rma
tio
nC
om
po
un
ds
1000’s
1
Candidate
Molecule
Development
Adapted from: A. Bak AAPS
Newsmagazine July 2014
DDDI provides a
collaborative and
interactive forum for
academic, industrial and
regulatory scientists
focused on issues at the
discovery/development
interface to improve the
discovery, optimization,
and successful
transitioning of
preclinical candidates
into clinical development Find out more at:
https://www.aaps.org/DDDI/
12
2016 Drug Design and Delivery Symposium
http://bit.ly/2016ddds
5/19/2016
7
Upcoming ACS Webinars www.acs.org/acswebinars
13
®
Contact ACS Webinars ® at [email protected]
Thursday, June 9, 2016
Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery
Thursday, June 2, 2016
Chemistry of Go: High Performance Elastomers Session 6 of the 2016 Material Science Series
Edmund Carnahan, R&D Fellow, Performance Plastics Division, Dow Chemical
Mark Jones, Executive External Strategy and Communications Fellow, Dow
Chemical
14
www.acs.org/acswebinars www.acs.org/acswebinars Slides available now! Recordings will be available to ACS members after one week
2016 Drug Design and Delivery Symposium
“Design of Deliverable Macrocycles”
The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS
Nick Meanwell Executive Director,
Discovery Chemistry,
Bristol-Myers Squibb
Scott Lokey Professor, University of California,
Santa Cruz and Director, UCSC
Chemical Screening Center
5/19/2016
8
Design of Deliverable Macrocycles
Scott Lokey Department of Chemistry & Biochemistry
University of California Santa Cruz
Scott Lokey University of California Santa Cruz
ACS Webinar, May 19, 2016 Session 5 of the 2016 Drug Design and Delivery Symposium
Dr. Matthew Naylor
Josh Schwochert
Cameron Pye
Chad Townsend
Dr. Andy Bockus
Dr. Akihiro ”Aki”
Furukawa
15
Dr. Taha Rezai
Dr. Tina (White) Doyle
Dr. Rushia Turner
0
200
400
600
800
1000
1200
0 500 1000 1500 2000
Bin
din
g S
ite
Su
rfa
ce
Are
a Å
2
Molecular Weight
Druggable Space
diffuse protein-protein interactions
Villar et al. Nature Chemical Biology 2014
Chemical space defined by target binding sites
pockets
clefts & grooves
Small molecules
Ro5
16
Mol. Wt
Biologics
5/19/2016
9
Biologics
Affinity, specificity
Cell permeability
extracellular
targets
17
0
200
400
600
800
1000
1200
0 500 1000 1500 2000
Bin
din
g S
ite
Su
rfa
ce
Are
a Å
2
Molecular Weight
Druggable Space
Small Molecules
Protein-Protein Interactions
macrocycles/ natural products
Villar et al. Nature Chemical Biology 2014
Druggable chemical space
bRo5
Natural product scaffolds can inform design in bRo5 space
Ro5
18
Biologics
5/19/2016
10
Compounds that emerge from DNA-encoded libraries often lack cell permeability
mRNA display libraries
Phage-encoded bicyclic peptides
Molecules 2013, 18, 3502-3528 Angew.Chem.Int.Ed. 2004, 43, 4848–4870
DNA-templated libraries
• Low-nM hits, but few have low-nM activity against intracellular targets
• Cyclization is generally not enough to impart favorable permeability
• Split-pool approaches permute scaffold (i.e., backbone) elements, but only a small percentage of scaffolds are expected to be permeable.
19
Cyclic peptide natural products
Affinity, specificity
Cell permeability
?
20
5/19/2016
11
21
Audience Survey Question
How does the MW distribution of cyclic peptide natural products compare to the MW distribution of FDA approved drugs?
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• They overlap
• They mostly overlap, although the natural products are skewed toward higher MW
• They barely overlap because the natural products are skewed so far toward higher MW
Cyclic peptide NPs vs. FDA-approved drugs
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 500 1000 1500 2000 2500 3000
fre
qu
en
cy
MW
FDA-approved drugs (n = 6500)
cyclic peptide NPs (n = 2387)
22
5/19/2016
12
Cell permeable cyclic peptide natural products: scaffold diversity
salinamide
didemnin B
argyrin
HUN-7293/cotransins cyclomarins
aureobasidin
Bockus & Lokey Curr Top Med Chem 13, 821-836 (2013).
polycyclic
N-methylation cyclodehydration
lariat structures
b-branching
SCBB H-bonding
depsipeptides
g-amino acids
23
1-NMe3
Thansandote, P. et al. Bioorg. Med. Chem. 23, 322-327 (2015).
GlaxoSmithKline
Lewis, I. et al. Int. J. Pept. Res. Ther., 1573-3149 (2014).
Novartis
Wang, C.K. et al. PNAS 111, p. 17504 (2014).
Univ. Queensland/Pfizer
Hewitt, W.M. et al. J. Am. Chem. Soc. 137, 715-721 (2015).
MedImmune/UCSC
Wang, et al, Eur. J. Med. Chem. 97, p. 202
Nielsen, et al., ChemBioChem (2015)
Univ. Queensland/Pfizer Univ. Queensland/Pfizer
Pe = 4.9 x 10-6 cm/s (MDCK cells) F = 28% (rat)
Nat. Chem. Biol. 7, (2011) 810-817 24
5/19/2016
13
Non-alpha backbone residues
didemnin B
Dr. Andrew Bockus
1NMe3
25
Cpd
PAMPA Pe
(x 10-6 cm/s)
MDCK Papp
(x 10-6 cm/s)
Solubility (uM)
HLM Clearance
(ug/min/mg) eLogD
1 1 0.8 200 188 6.0
4 7 7.7 600 30 6.9
5 2 1.4 600 31 6.1
6 20 9.0 200 290 6.3
1NMe3 10 4.9 6.4 110 -
Stereochemistry affects physicochemical properties
1
%F (rat) = 21%
Bockus, A. T., et al. J. Med. Chem. 2015, 58, p 4581
4 5 6
26
5/19/2016
14
Hydrogen bonding and passive permeability
1
5 6
3 H-bonds
Pe = 1 x 10-6 cm/s
4 H-bonds
Pe = 7 x 10-6 cm/s
4 H-bonds
Pe = 20 x 10-6 cm/s
2 H-bonds
Pe = 2 x 10-6 cm/s
4
27
Josh Schwochert
Dr. Akihiro ”Aki” Furukawa
Chad Townsend
Effect of side chain variation
28
5/19/2016
15
29
Sub-01
Sub-06
Sub-02
Sub-07
Sub-03
Sub-08
Sub-04
Sub-09
Sub-05
Sub-10
NH
N
O
O
NO
NO
O
HN
N
O
Me
R3
R2
R4
R4
R3
R2
Effect of side chain variation
30
5/19/2016
16
Side chain effects: steric shielding and conformation
Hewitt et al. JACS (2015)
Dr. William Hewitt
31
Dr. William Hewitt
Side chain effects: steric shielding and conformation
32 Hewitt et al. JACS (2015)
5/19/2016
17
Side chain effects: steric shielding and conformation
33 Hewitt et al. JACS (2015)
Hewitt et al. JACS 2014, 137, p. 715
Side chain effects: steric shielding and conformation
34
5/19/2016
18
Hewitt et al. JACS 2014, 137, p. 715
Side chain effects: steric shielding and conformation
35
36
Audience Survey Question
How would you expect a single Isoleucine-to-Leucine substitution to affect the aqueous solubility of this cyclic peptide?
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
Ile Leu
5/19/2016
19
37
Audience Survey Question
How would you expect a single Isoleucine-to-Leucine substitution to affect the aqueous solubility of this cyclic peptide?
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• No effect
• A small but measurable effect due to the subtle lipophilicity difference between Ile and Leu
• A large increase: The Leu compound should be significantly more soluble than the Ile compound
• A large decrease: The Leu compound should be significantly less soluble than the Ile compound
NH
NH
NH
favored in water
favored in chloroform
not sampled
X
c-rotation
(side chain)
f/y rotation(backbone)
O
O
ONH
NH
O
O
NH
O
NH
NH
O
ONH
NH
O
ONH
O
NH
O
steric clash
c-rotation
(side chain)
f/y rotation(backbone)
Caco-2: 14 x 10-6 cm/s Aq. Sol: 8 µM
Caco-2: 19 x 10-6 cm/s Aq. Sol: 111 µM Bockus et al. J. Med. Chem. 2015, 58, p. 7409
Side chain branching has dramatic effect on aqueous solubility
38
5/19/2016
20
Addressing the size limit… 1NMe3 vs. CSA
CSA
MW = 1202
1NMe3
MW = 755
Fouché, et al., ChemMedChem 2016, 11, 1 – 13 (Novartis)
MW ~ 1000, F = 100% (rat)
39
40
Audience Survey Question
The molecular weight (or size) “ceiling” for achieving passive membrane permeability relates to?
ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT
• The free energy associated with forming cavities in the membrane
• Opposition to the lateral pressure inside the ordered “barrier domain” at the center of the bilayer
• The radius-dependent (i.e., Stokes-Einstein) diffusion of a solute through a viscous medium
• All of the above
• None of the above
5/19/2016
21
Full lipophilicity scan library on 8, 9, 10-mers
Nle Nva Abu Ala
X =
Cameron Pye
bRo5
41
octa nona
deca
0123456
0 1 2 3 4 5 6 7
Pe(10-6 cm/s)
AlogP
octa
nona
deca
PAMPA permeability vs. AlogP
42
5/19/2016
22
octa
0
0.2
0.4
0.6
0.8
1
-9.5
-8.5
-7.5
-6.5
-5.5
-4.5
-3 -2 -1 0 1 2 3
Solu
bili
ty
logP
e
logK
Octapeptides
logP0 Intrinsic permeability
corrected for solubility
43
𝑃0 =𝐾ℎ𝑐/𝑤𝐷
𝛿
𝐿𝑜𝑔𝑃0
𝛿𝐾ℎ𝑐/𝑤= 𝑳𝒐𝒈𝑫
-12
-10
-8
-6
-4
-2
0
6 8 10 12
Mol. Radius (or V 0.33) (Å)
Lo
gD (
cm2/s
)
𝐷 = 𝑘𝑇
6𝜋𝜂𝑟
44
5/19/2016
23
𝑃0 =𝐾ℎ𝑐/𝑤𝐷
𝛿
𝐿𝑜𝑔𝑃0
𝛿𝐾ℎ𝑐/𝑤= 𝑳𝒐𝒈𝑫
[CELLRANGE]
[CELLRANGE]
[CELLRANGE]
[CELLRANGE]
[CELLRANGE]
[CELLRANGE]
[CELLRANGE] [CELLRANGE]
[CELLRANGE]
-12
-10
-8
-6
-4
-2
0
6 8 10 12
Mol. Radius (or V 0.33) (Å)
Lo
gD (
cm2/s
)
45
Conclusions
IMHB desolvation energy
vs.
1. Scaffolds can achieve permeability by adopting non-polar conformations. This phenomenon does not always correlate with intramolecular hydrogen bonding, but often it does.
2. Excellent permeability can be achieved in compounds with novel natural and synthetic backbone elements.
3. Side chains can impact permeability and solubility in both simple and complex ways, through effects on overall lipophilicity as well as more subtle conformational effects.
4. The impact of MW remains a mystery.
polycyclic
N-methylation cyclodehydration
lariat structures
b-branching
SCBB H-bonding
depsipeptides
g-amino acids NH
NH
NH
favored in water
favored in chloroform
not sampled
X
c-rotation
(side chain)
f/y rotation(backbone)
O
O
ONH
NH
O
O
NH
O
NH
NH
O
ONH
NH
O
ONH
O
NH
O
steric clash
c-rotation
(side chain)
f/y rotation(backbone)
1NMe3
stylissamideG
cordyheptapeptinB
scytalidamide
cylindrocyclin
CSA_Bmt2Leu
VumonDigoxin
Xifaxan
-12
-10
-8
-6
-4
-2
0
6 8 10 12
Mol.Radius(orV0.33)(Å) 46
5/19/2016
24
Acknowledgements
UCSC
Prof. Matt Jacobson (UCSF)
Other lab members
Rushia Turner
Walter Bray
Will Hewitt
Dustin Wride
Victoria Klein
Tannia Lau
Spiros Liras David Price Alan Mathiowetz
Joshua Schwochert Maria Bednarek
Cameron Pye Lauren Goodrich Thomas Albert Jigar Patel Eric Sullivan Victor Lyamichev
Matthew Naylor Maria Blanco Prashant Desai Isabel Gonzalez Jaclyn Barrett
Akihiro ”Aki” Furukawa Dr. Tohru Takahashi Dr. Takeshi Honda
David Earp, Matthew Jacobson, Siegfried Leung, Pablo Garcia, Mahesh Ramanaseshan Cayla McEwen
47
48
www.acs.org/acswebinars www.acs.org/acswebinars Slides available now! Recordings will be available to ACS members after one week
2016 Drug Design and Delivery Symposium
“Design of Deliverable Macrocycles”
The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS
Nick Meanwell Executive Director,
Discovery Chemistry,
Bristol-Myers Squibb
Scott Lokey Professor, University of California,
Santa Cruz and Director, UCSC
Chemical Screening Center
5/19/2016
25
49
2016 Drug Design and Delivery Symposium
http://bit.ly/2016ddds
Upcoming ACS Webinars www.acs.org/acswebinars
50
®
Contact ACS Webinars ® at [email protected]
Thursday, June 9, 2016
Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery
Thursday, June 2, 2016
Chemistry of Go: High Performance Elastomers Session 6 of the 2016 Material Science Series
Edmund Carnahan, R&D Fellow, Performance Plastics Division, Dow Chemical
Mark Jones, Executive External Strategy and Communications Fellow, Dow
Chemical
5/19/2016
26
51
www.acs.org/acswebinars www.acs.org/acswebinars Slides available now! Recordings will be available to ACS members after one week
2016 Drug Design and Delivery Symposium
“Design of Deliverable Macrocycles”
The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS
Nick Meanwell Executive Director,
Discovery Chemistry,
Bristol-Myers Squibb
Scott Lokey Professor, University of California,
Santa Cruz and Director, UCSC
Chemical Screening Center
Candidate
Knowledge
Info
rma
tio
nC
om
po
un
ds
1000’s
1
Candidate
Molecule
Development
Adapted from: A. Bak AAPS
Newsmagazine July 2014
DDDI provides a
collaborative and
interactive forum for
academic, industrial and
regulatory scientists
focused on issues at the
discovery/development
interface to improve the
discovery, optimization,
and successful
transitioning of
preclinical candidates
into clinical development Find out more at:
https://www.aaps.org/DDDI/
5/19/2016
27
Find out more about the ACS MEDI Division! www.acsmedchem.org
53
Join the ACS Division of Medicinal Chemistry Today!
For $25 ($10 for students), You Will Receive:
• A free copy of our annual medicinal chemistry review
volume (over 600 pages, $160 retail price)
• Abstracts of MEDI programming at national meetings
• Access to student travel grants and fellowships
Be a featured fan on an upcoming webinar! Write to us @ [email protected]
54
How has ACS Webinars benefited you?
®
“I really appreciated the insight into the mind of
current leaders in medicinal chemistry, particularly
the encouragement to gain experience in a variety
of areas with the focus on working on scientific
challenges. It helps to remove limitations I'd
placed on myself based on my areas of synthetic
experience.”
Crystal O’Neil,
Scientist, Chemist, Research and Development
Quote in reference to: http://www.acs.org/content/acs/en/acs-
webinars/drug-discovery/drug-career.html
5/19/2016
28
55
facebook.com/acswebinars
@acswebinars
youtube.com/acswebinars
Search for “acswebinars” and connect!
Benefits of ACS Membership
56 http://bit.ly/ACSjoin
Chemical & Engineering News (C&EN) The preeminent weekly news source.
NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.
NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.
5/19/2016
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ACS Webinars does not endorse any products or
services. The views expressed in this
presentation are those of the presenter and do
not necessarily reflect the views or policies of the
American Chemical Society.
®
Contact ACS Webinars ® at [email protected]
Upcoming ACS Webinars www.acs.org/acswebinars
58
®
Contact ACS Webinars ® at [email protected]
Thursday, June 9, 2016
Ice Cream Chemistry
Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison
Maya Warren, Food Scientist, Cold Stone Creamery
Thursday, June 2, 2016
Chemistry of Go: High Performance Elastomers Session 6 of the 2016 Material Science Series
Edmund Carnahan, R&D Fellow, Performance Plastics Division, Dow Chemical
Mark Jones, Executive External Strategy and Communications Fellow, Dow
Chemical