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“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

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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

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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

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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

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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

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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

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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

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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

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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

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Side chain effects: steric shielding and conformation

Hewitt et al. JACS (2015)

Dr. William Hewitt

31

Dr. William Hewitt


32 Hewitt et al. JACS (2015)

5/19/2016

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33 Hewitt et al. JACS (2015)

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


34

5/19/2016

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


35

36


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


Ile Leu

5/19/2016

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37


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

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)


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

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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


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

5/19/2016

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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

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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

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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)


O

O

ONH

NH

O

O

NH

O

NH

NH

O

ONH

NH

O

ONH

O

NH

O

steric clash

c-rotation

(side chain)


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











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Ice Cream Chemistry







Chemical

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51











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:



5/19/2016

27

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

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Join the ACS Division of Medicinal Chemistry Today!

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• 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

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Search for “acswebinars” and connect!

Benefits of ACS Membership

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