medicinal chemistry research

MEDICINAL CHEMISTRY RESEARCH

Development of TK inhibitors

Andrej Boháč

PDF created with pdfFactory Pro trial version www.pdffactory.com

http://www.pdffactory.com

Protein kinases (PK) – enzymes that transfer PO3 group to proteins

Protein Kinasesdirect the activity of up to30% of cellular proteins,orchestrate the activity ofalmost all cellularprocesses

Kinom (the kinase dendrogram)518 hu-PK collected in 7major groups. 6 subgroupsare serine / threonine kinasisand 1 group are TKs thatphosphorylate tyrosine AAresidues.

Manning G et al. 2002 Science 298 1912–34.KINOME shows diversity of catalytic domains

in 518 hu-PKPDF created with pdfFactory Pro trial version www.pdffactory.com


OUR RECENT RESULTS – SBCP / nM1. we developed para substituted AAZ-based inhibitors / and uncovered SBCP

(Salt Bridge Containing Pocket)

Struct. Chem. 2011, 22, 635. + unpublished resultsPDF created with pdfFactory Pro trial version www.pdffactory.com


2. We developed chimeric nM inhibitor / 34 VEGFR2 TK analysed / rare inactive (DFG-out) TK A-loop opened variants uncovered

European Journal of Medicinal Chemistry 72 2014 146-159.

OUR RECENT RESULTS – nM / rare variants of TKs



OUR RECENT RESULTS – isosteric VEGFR2 modulators / Spider-like molecules3. Development of YNAMIDEs based triazolic VEGFR2 modulators/ Spider-like

(CRAAC) molecules proposed

ONH

N

O

N

S OO

AAZ (FW: 435.50)

IC50 = 22 nM (VEGFR2)docking score -50.3 (-51.6)

ISOSTERIC REPLACEMENT

Spider-like (CRAAC) molecules

NOVELTY, SYNTH FEASIBILITY



OUR RESEARCH in progress

4. Regioisomeric Bioisostery (OXAZOLES, BENZOXAZOLES, CARBOXAMIDES)

5. Carboxamide VEGFR2 modulators

6. Benzoxazole VEGFR2 modulators

7. TAM TK (Mer TK) inhibitors development from 8 M structures(in vitro TK and cell assays)

8. 1,2,3-triazolic TK inhibitiors , In situ Click Chemistry, [2+2+2] cyclotrimerisations etc.

ONH

N

O

SO O

N

AAZ (17 nM (VEGFR2), PDB: 1Y6A)

overall yield ca 10 %stability, novelty

NH

N

O

S OO

O

ON

R



Project: Methodology for a simple benzoxazolesynthesis useful for VEGFR2 inhibitors

development

Biomagi RNDr. Ambroz Almássy, PhD.PDF created with pdfFactory Pro trial version www.pdffactory.com


Project rationale



Proposed sequential and one pot methodology

HO

ONH2

OH

+

AI

O

NHOH

EDCHOBt

A/ Synthesis of AmidicIntermediate and optimisation of its cyclisation

N

O

BO-PR

DEAD / PPh3

HO

ONH2

OH

+

AI

O

NHOH

EDCHOBt EDC / PPh3

Me3Al

EDC / PPh3

B/ one pot Synthesis of BenzoxazOl-PRoduct directly from aminophenol and ArCOOH

or DEAD / PPh3

Me3Al (excess, heating, ?)

Me3Al(excess, heating, ?)

1d

1a1b

1c

2c

2aaccording the lit. by this way also 8 %of benzoxazole was observed

2b

3H+

or Deoxo-Fluor reagent NSF3

OO 2d



Mechanism of Mitsunobu ring closure



Twice RegBioisostery

O

NHO

SOO

N

NO

Z

O

NHO

SOO

N

NO

Z

N

NHO

SOO

O

NO

Z

N

NHO

SOO

O

NO

Z

RegBio => four novel compounds possessing similar bioactivity

O

NHO

SOO

N

NO

Z

O

NHO

SOO

N

NO

NNHO

SOO

O

N

O

NNHO

SOO

O

N

OZ Z

Z



in Silico predicted structures / Biomagi

O

NHO

SOO

N

N

OO

O

-53.28 (1Y6B)4 HB, FW 457, xlogP 3.6charges 0, NRB 8

O

NHO

SOO

N

N

O O

O

-53.25 (1Y6B)4 HB, FW 457, xlogP 3.6charges 0, NRB 8

O

NHO

SOO

N

N

OHO

O

-48.90 (1Y6B)4 HB + ?ionic, FW 443, xlogP 3.3charges -1, NRB 7

NH

N

O

S

O

OO NO

OHO

-47.81 (1Y6B)4 HB + ?ionic, FW 443xlogP 3.3, charges -1, NRB 7

HONH2OH

H2N

COOMe COOMe

[CPR]250 mg / 51 E

[CPR]250 mg / 51 E

HONH2OH

H2N

COOH COOH

[1571-72-8]5 g / 29 E

[2374-03-0]5 g / 81 E



Aims for a Bc Diploma Work

1. Search of databases and literature for a direct preparation of benzoxazolesfrom karboxylic acids. Select the best methods for our purposes.

2. Develop of synthetic methodology for bezoxazole preparation directly fromArCOOH by simple and mild reaction conditions

3. Synthesis of some predicted benzoxazolic VEGFR2 inhibitors



AcknowledgementDoc. RNDr. Marta Sališová, PhD. (retired)RNDr. Ambroz Almássy, PhD.p. Miroslava MatejováMgr. Lucia Kušnierová – Kováčiková, PhD. (SAV)Mgr. Lucia Lintnerová, PhD. (FaF UK)Mgr. Jana HolekšiováMgr. Juraj DobiašMgr. Peter ŠramelBc. Miroslav MurárKristína FerenczyováMarek OndrušMatúš HlaváčIvan Mäsiar

Biomagi, APVV, VEGA, COST CM1106



Biological Target



medicinal chemistry research

Documents