Design of Deliverable Macrocycles

5/19/2016

We will begin momentarily at 2pm ET

Slides available now! Recordings will be available to ACS members after one week.

www.acs.org/acswebinars Contact ACS Webinars ® at [email protected]

1

Have Questions?

“Why am I muted?” Don’t worry. Everyone is muted except the presenter and host. Thank you and enjoy the show.

Type them into questions box! Contact ACS Webinars ® at [email protected]

2

1

5/19/2016

Have you discovered the missing element?

http://bit.ly/ACSjoin Find the many benefits of ACS membership! 3

Benefits of ACS Membership 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.

http://bit.ly/ACSjoin

4

2

5/19/2016

Let’s get Social…post, tweet, and link to ACS Webinars during today’s broadcast!

facebook.com/acswebinars

@acswebinars

Search for “acswebinars” and connect!

5

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.” Quote in reference to: http://www.acs.org/content/acs/en/acswebinars/drug-discovery/drug-career.html

Crystal O’Neil, Scientist, Chemist, Research and Development

Be a featured fan on an upcoming webinar! Write to us @ [email protected]

6

3

5/19/2016

facebook.com/acswebinars @acswebinars youtube.com/acswebinars

Search for “acswebinars” and connect! 7

Learn from the best and brightest minds in chemistry! Hundreds of webinars presented by subject matter experts in the chemical enterprise. Recordings are available to current ACS members one week after the Live broadcast date. www.acs.org/acswebinars ®

Broadcasts of ACS Webinars continue to be available to the general public LIVE every Thursday at 2pm ET!

www.acs.org/acswebinars

8

4

5/19/2016

ChemIDP.org

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 Find out more about the ACS MEDI Division! www.acsmedchem.org

10

5

Information

5/19/2016

Candidate Knowledge

Compounds

Development

Candidate Molecule

1 1000’s

Adapted from: A. Bak AAPS Newsmagazine July 2014

Find out more at: https://www.aaps.org/DDDI/

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

2016 Drug Design and Delivery Symposium

http://bit.ly/2016ddds

12

6

5/19/2016

®

Upcoming ACS Webinars www.acs.org/acswebinars 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

Thursday, June 9, 2016

Ice Cream Chemistry Rich Hartel, Professor of Food Engineering, University of Wisconsin-Madison Maya Warren, Food Scientist, Cold Stone Creamery

13

Contact ACS Webinars ® at [email protected]

2016 Drug Design and Delivery Symposium “Design of Deliverable Macrocycles”

Scott Lokey

Nick Meanwell

Professor, University of California, Santa Cruz and Director, UCSC Chemical Screening Center

Executive Director, Discovery Chemistry, Bristol-Myers Squibb

Slides available now! Recordings will be available to ACS members after one week

www.acs.org/acswebinars The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

14

7

5/19/2016

Design of Deliverable Macrocycles Scott Lokey University of California Santa Cruz ACS Webinar, May 19, 2016 Session 5 of the 2016 Drug Design and Delivery Symposium

Scott Lokey Dr. Taha Rezai

Department of Chemistry & Biochemistry Dr. Matthew Josh Cameron Chad University ofNaylor California Santa Cruz Schwochert Pye

Dr. Akihiro ”Aki” Furukawa Townsend Dr. Andy Bockus

Dr. Rushia Turner Dr. Tina (White) Doyle 15

Chemical space defined by target binding sites Druggable Space

clefts & grooves

pockets

Binding Site Surface Area Å2

diffuse protein-protein 1200 interactions

Biologics

1000 800 600 Ro5

400

Small molecules

200

0 0

Villar et al. Nature Chemical Biology 2014

500

1000 1500 Molecular Weight Mol. Wt

2000

16

8

5/19/2016

Biologics Affinity, specificity extracellular targets

Cell permeability

17

Natural product scaffolds can Druggable chemical space inform Druggable designSpace in bRo5 space

Binding Site Surface Area Å2

1200

Biologics

Protein-Protein Interactions

1000 800

bRo5

macrocycles/ natural products

600 Ro5

400

Small Molecules

200

0 0

500

1000 1500 Molecular Weight

Villar et al. Nature Chemical Biology 2014

2000 18

9

5/19/2016

Compounds that emerge from DNA-encoded libraries often lack cell permeability

mRNA display libraries

DNA-templated libraries Phage-encoded bicyclic peptides

• 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.

Molecules 2013, 18, 3502-3528 Angew.Chem.Int.Ed. 2004, 43, 4848–4870

19

Cyclic peptide natural products

Affinity, specificity

?

Cell permeability

20

10

5/19/2016

Audience Survey Question ANSWER THE QUESTION ON BLUE SCREEN IN ONE MOMENT

How does the MW distribution of cyclic peptide natural products compare to the MW distribution of FDA approved drugs? • 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

21

Cyclic peptide NPs vs. FDA-approved drugs 0.35

FDA-approved drugs (n = 6500)

frequency

0.3 0.25 0.2 0.15

cyclic peptide NPs (n = 2387)

0.1 0.05 0 0

500

1000

1500

2000

2500

3000

MW 22

11

5/19/2016

Cell permeable cyclic peptide natural products: scaffold diversity polycyclic

SCBB H-bonding

aureobasidin

salinamide

cyclodehydration

argyrin

N-methylation

g-amino acids

HUN-7293/cotransins

b-branching

depsipeptides

didemnin B

lariat structures

cyclomarins

Bockus & Lokey Curr Top Med Chem 13, 821-836 (2013).

23

1-NMe3 GlaxoSmithKline

Univ. Queensland/Pfizer

Thansandote, P. et al. Bioorg. Med. Chem. 23, 322-327 (2015).

Wang, C.K. et al. PNAS 111, p. 17504 (2014).



Wang, et al, Eur. J. Med. Chem. 97, p. 202

Nielsen, et al., ChemBioChem (2015)

MedImmune/UCSC

Novartis Lewis, I. et al. Int. J. Pept. Res. Ther., 1573-3149 (2014).

Pe = 4.9 x 10-6 cm/s (MDCK cells) F = 28% (rat)

Nat. Chem. Biol. 7, (2011) 810-817

Hewitt, W.M. et al. J. Am. Chem. Soc. 137, 715-721 (2015).

24

12

5/19/2016

Non-alpha backbone residues

didemnin B

Dr. Andrew Bockus

1NMe3 25

Stereochemistry affects physicochemical properties

1

4 %F (rat) = 21%

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

-

5

Bockus, A. T., et al. J. Med. Chem. 2015, 58, p 4581

6

26

13

5/19/2016

Hydrogen bonding and passive permeability

4

1 3 H-bonds Pe = 1 x 10-6 cm/s

5

4 H-bonds Pe = 7 x 10-6 cm/s

6

2 H-bonds Pe = 2 x 10-6 cm/s 4 H-bonds Pe = 20 x 10-6 cm/s

27

Effect of side chain variation

Josh Schwochert

Dr. Akihiro ”Aki” Furukawa

Chad Townsend

28

14

5/19/2016

Effect of side chain variation

R4

R3

O

Me N

N H O N

R4

R2

O

N O

O N

H N

R2 O

R3

Sub-01

Sub-02

Sub-03

Sub-04

Sub-05

Sub-06

Sub-07

Sub-08

Sub-09

Sub-10

29

30

15

5/19/2016

Side chain effects: steric shielding and conformation Dr. William Hewitt

Hewitt et al. JACS (2015)

31

Side chain effects: steric shielding and conformation Dr. William Hewitt


32

16

5/19/2016

Side chain effects: steric shielding and conformation


33


Hewitt et al. JACS 2014, 137, p. 715

34

17

5/19/2016


Hewitt et al. JACS 2014, 137, p. 715

35


How would you expect a single Isoleucine-to-Leucine substitution to affect the aqueous solubility of this cyclic peptide? Ile

Leu

36

18

5/19/2016


How would you expect a single Isoleucine-to-Leucine substitution to affect the aqueous solubility of this cyclic peptide? • 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 37

Side chain branching has dramatic effect on aqueous solubility steric clash

H N

H N

O

H N

(side chain)

O

f/y rotation O H N

O

(backbone)

H N

c-rotation O

X

O

H N

not sampled

O H N

(side chain)

H N

H N

O

c-rotation

O

f/y rotation O

(backbone)

H N

O H N

Caco-2: 14 x 10-6 cm/s Aq. Sol: 8 µM

O

H N

favored in chloroform

Caco-2: 19 x 10-6 cm/s Aq. Sol: 111 µM

favored in water

Bockus et al. J. Med. Chem. 2015, 58, p. 7409

38

19

5/19/2016

Addressing the size limit… 1NMe3 vs. CSA

CSA

MW = 1202

1NMe3

MW = 755 MW ~ 1000, F = 100% (rat) Fouché, et al., ChemMedChem 2016, 11, 1 – 13 (Novartis)

39


The molecular weight (or size) “ceiling” for achieving passive membrane permeability relates to? • 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 40

20

5/19/2016

Full lipophilicity scan library on 8, 9, 10-mers

X=

bRo5

Cameron Pye Nle

Abu

Nva

Ala

41

nona

octa

deca

Pe(10 -6 cm/s)

PAMPA permeability vs. AlogP

6 5 4 3 2 1 0

octa nona deca 0

1

2

3

4

5

6

7

AlogP 42

21

5/19/2016

logP0

Intrinsic permeability corrected for solubility

Octapeptides

1

-4.5 logPe

octa

0.6

-6.5 -7.5

0.4

-8.5

0.2

-9.5

Solubility

0.8

-5.5

0 -3

-2

-1

0 logK

1

2

3

43

𝑃0 =

𝐾ℎ𝑐/𝑤 𝐷 𝛿

0

𝑃0 𝐿𝑜𝑔 = 𝑳𝒐𝒈𝑫 𝛿𝐾ℎ𝑐/𝑤

𝐷=

LogD (cm2/s)

-2

𝑘𝑇 6𝜋𝜂𝑟

-4 -6 -8 -10 -12 6

8

10

12

Mol. Radius (or V 0.33) (Å) 44

22

5/19/2016

𝑃0 =

0

𝑃0 = 𝑳𝒐𝒈𝑫 𝛿𝐾ℎ𝑐/𝑤

-2

LogD (cm2/s)

𝐿𝑜𝑔

𝐾ℎ𝑐/𝑤 𝐷 𝛿

[CELLRANGE] [CELLRANGE] [CELLRANGE]

-4

[CELLRANGE]

-6

[CELLRANGE]

[CELLRANGE]

[CELLRANGE]

-8

[CELLRANGE] [CELLRANGE]

-10 -12 6

8

10

12

Mol. Radius (or V 0.33) (Å) 45

Conclusions 1. Scaffolds can achieve permeability by adopting non-polar conformations. This phenomenon does not always correlate with intramolecular hydrogen bonding, but often it does.

vs. steric clash O

f/y rotation

H N

O

polycyclic O

(backbone) SCBB H-bonding

X

H N

O

not sampled

depsipeptides

lariat structures

3. Side chains can impact permeability c-rotation and solubility in both simple and (side chain) O complex ways, through effects on H O N overall lipophilicity as well as more favored in chloroform subtle conformational effects.

H N

b-branching

cyclodehydration

N-methylation

g-amino acids

f/y rotation (backbone)

H N

H N

O H N

O

O H N

H N

2. Excellent permeability can Obe H N achieved in compounds with novel natural and synthetic backbone elements.

(side chain)

H N

c-rotation O

desolvation energy

IMHB

O

H N

0

-2

Vumon Digoxin Xifaxan

-4

4. The impact of MW remains a mystery.

-6

favored in water

scytalidamide cordyheptapep tin B

1NMe3

CSA_Bmt2Leu

-8

stylissamide G cylindrocyclin

-10 -12 6

8

10

Mol. Radius (or V 0.33) (Å)

12

46

23

5/19/2016

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

Akihiro ”Aki” Furukawa Dr. Tohru Takahashi Dr. Takeshi Honda

Matthew Naylor Maria Blanco Prashant Desai Isabel Gonzalez Jaclyn Barrett

David Earp, Matthew Jacobson, Siegfried Leung, Pablo Garcia, Mahesh Ramanaseshan Cayla McEwen

Joshua Schwochert Maria Bednarek

Cameron Pye Lauren Goodrich Thomas Albert Jigar Patel Eric Sullivan Victor Lyamichev

47


Scott Lokey

Nick Meanwell




www.acs.org/acswebinars The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

48

24

5/19/2016

2016 Drug Design and Delivery Symposium

http://bit.ly/2016ddds

49

®






50

25

5/19/2016


Scott Lokey

Nick Meanwell




www.acs.org/acswebinars

Information

The 2016 DDDS is co-produced with ACS Division of Medicinal Chemistry and the AAPS

Candidate Knowledge

Compounds

Development

Candidate Molecule

1 1000’s

Adapted from: A. Bak AAPS Newsmagazine July 2014

Find out more at: https://www.aaps.org/DDDI/

51

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

26

5/19/2016

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 Find out more about the ACS MEDI Division! www.acsmedchem.org

How has ACS Webinars benefited you?

53

®

“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.” Quote in reference to: http://www.acs.org/content/acs/en/acswebinars/drug-discovery/drug-career.html

Crystal O’Neil, Scientist, Chemist, Research and Development

Be a featured fan on an upcoming webinar! Write to us @ [email protected]

54

27

5/19/2016

facebook.com/acswebinars @acswebinars youtube.com/acswebinars

Search for “acswebinars” and connect! 55

Benefits of ACS Membership 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.

http://bit.ly/ACSjoin

56

28

5/19/2016

®

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.


57

®






58

29

Design of Deliverable Macrocycles

Recommend Documents