MDM2-Targeted Library

MDM2-Targeted Library Medicinal and Computational Chemistry Dept., ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121 USA, Service: +1 877 ChemDiv, Tel: +1 858-794-4860,

Fax: +1 858-794-4931, Dr. Yan A. Ivanenkov, e-mail: [email protected]

PREAMBLE P53, a nuclear transcription factor and its negative regulator MDM2 consists of the most intensely studied protein-protein interactions (PPI) with a group of small molecular weight inhibitors described and many more disclosed in patent literature. Around 22 million people are currently living with a tumor affected by p53 and while p53 mutations are very common in human tumors it remains wildtype in approximately 50% of cancer patients. Cancer cells have been revealed to overexpress the negative regulators of p53, MDM2 and/or MDMX, causing a severe decrease in p53 expression thereby preventing the apoptosis of malignant cells. Inhibitors of MDM2/p53 PPI are currently described as promising drug candidates against various types of cancer.

mailto:[email protected]

① Transient protein-protein interactions (PPIs) are essential components in cellular signaling pathways as well as in important processes such as viral infection, replication, cancer, and immune suppression; ② The unknown or uncharacterized PPIs involved in this networks often represent compelling therapeutic targets for drug discovery; ③ To date, the main strategies for discovery of small molecule modulators of PPIs are typically limited to structurally characterized targets; ④ Recent developments in molecular scaffolds that mimic the side chain display of peptide secondary structures have yielded effective designs, but few screening libraries of such are available to interrogate PPI targets; ⑤ Recently, we have initiated an internal program to prepare a comprehensive small molecule library designed to mimic the three major recognition motifs that mediate PPIs (α-helix, β-turn, and β-strand). Three sub-libraries are built around divers templates designed to mimic each such secondary structure and substituted with all triplet combinations of groups representing the 20 natural amino acid side chains; ⑥ When combined, the three libraries represent the common start-point for mimicking the key interaction and recognition residues of most targetable PPIs; ⑦ We generally expect that the screening of these libraries will not only provide lead structures against α-helix- or β-turn-mediated protein-protein or peptide-receptor interactions, even if the nature of the interaction is unknown, but also yield key insights into the recognition motif (α-helix or β-turn) and identify the key residues mediating the interaction; ⑧ The library presented is specifically focused against MDM2 protein and related PPI, including the key p53/MDM2 interface.

Protein-Protein Interactions as promising drug “target”

p53 suppresses the formation of tumors and plays an essential role in guarding cells in response to various stresses, such as DNA damage, or hypoxia, by inducing cell cycle arrest, repair, or apoptosis. If p53 functionality is impaired it can no longer prevent damaged cells from multiplying and passing mutated genes to the next generation and allows these processes to go unregulated.

p53 and MDM2 form an auto-regulatory feedback loop. p53 stimulates the expression of MDM2; MDM2 inhibits p53 activity because it blocks its transcriptional activity, favours its nuclear export and

stimulates its degradation. Different cellular signals, such as DNA-damage or oncogene activation, induce p53 activation. DNA damage favours p53 phosphorylation, preventing its association with

MDM2. Activated oncogenes activate the ARF protein, which prevents the MDM2-mediated degradation of p53. Similarly, inhibitors of the p53–MDM2 interaction should activate p53 tumour-

suppressor activity in tumour cells that express wild-type p53. These compounds, because they bind to MDM2, could also affect the p53-independent activities of MDM2

p53/MDM2 network

STRUCTURAL BIOLOGY OF MDM2 P53 INTERACTION

The 3D structure of MDM2 with and without p53 derived peptides and small molecules is extensively elaborated with more than 20 high resolution X-ray and NMR structures available in the Protein Data Bank. In a seminal work in 1996 Pavletich et al. described the first crystal structure of the interaction of p53/MDM2.

Key amino acids of p53 (yellow) mounted on an alpha-helix bound to MDM2 (grey) (PDB-ID: 1YCR)

MDM2 has a deep and structured binding pocket for p53. The binding pocket measures only 18 A along the long edge; the size of a typical small molecule. The p53/MDM2 complex has a ‘‘hot spot triad’’ made up of p53’s Trp23, Leu26, and Phe19. The three hydrophobic amino acids fit into three shape and electrostatic complementary hydrophobic pockets, and the indole nitrogen of p53’s Trp23 forms a hydrogen bond with Leu54 of MDM2 (Met53 in MDMX). In fact much of the binding energy resides in these three amino acids. Alanine scan studies show that mutation of any of the three hot-spot amino acids destroys the affinity between p53 and MDM2. A prerequisite for high affinity MDM2 antagonists is therefore that certain moieties of the molecule must mimic the three amino acids of p53’s hot spot triad Trp23, Leu26, and Phe19. In fact an illustrative model termed ‘‘three finger pharmacophore’’ has been created

˃ The concentration and activity of p53 protein in a cells are low and subjected to tight control both during stress and under normal physiological conditions. MDM2 mediated degradation regulates unstressed cell, via the ubiquitin-proteasome pathway (regulation of p53 stability), and by inactivation of the p53 transcriptional activity. In addition p53 activity is modified by MDM2 and MDMX by transporting p53 into cytoplasm, away from nuclear DNA making the activity of p53 as a transcription factor out of reach; ˃ MDM2 is a special example of a protein that regulates p53 through an auto-regulatory feedback loop, in which p53 also regulates MDM2; ˃ Drugs designed to inhibit the MDM2/p53 protein-protein interaction are able to reactivate p53 activity, leading to an antitumor effect in model systems; ˃ Currently, there are several MDM2/p53 inhibitors, such as the benzodiazepinediones, the spiro-oxindoles and the cis-imidazolines (nutlins). These prototype compounds have been used as experimental probes to determine the cellular consequences of activation of p53 in a variety of genetic backgrounds; ˃ The results to date indicate that small-molecule inhibitors of the MDM2/p53 interaction have great promise as antitumor agents, either as single agents or in combination with cytotoxic chemotherapy.

MDM2/p53 focus

Nutlin-3 Hoffmann la Roche

These compounds displaced p53 from MDM2 with an IC50 in the

100 to 300 nM range. Compounds were first screened as a racemic mixture however

upon separation of enantiomers via use of a chiral column it was shown that (-) Nutlin-3 was 150

times more active than (+) Nutlin-3.

Crystallographic studies showed the mode of binding of the Nutlin scaffold.

Co-crystal of Nutlin 2 (purple) (PDB-ID: 1RV1) bound to MDM2 (grey), superimposed on key amino acids of p53/MDM2 co-crystal

RG7112 (RO5045337) Roche's Nutlin compound currently in clinical trial

One of the bromophenyl moieties sits deeply in the Trp23 pocket, while the other bromophenyl

moiety sits in the Leu26 pocket. The ethyl ether side chain occupies the Phe19 pocket and the backbone of the imidazoline scaffold mimics the

alpha helix of p53

NUTLIN analogs

Spirooxindoles discovered using computational techniques

Using of p53’s Trp23 as a starting point and looking for molecules to mimic the interaction of p53’s Trp23 to MDM2

In addition to the indole ring, the oxindole was also found to be a perfect mimic for Trp23 in both the hydrogen bond formations and the potential hydrophobic interaction with MDM2.

Substructure searches of natural products containing oxindole rings allowed them to identify a number of natural products, including natural alkaloids such as spirotryprostatin A and alstonisine which contain a spirooxindole core

The spiroindole ring provides a rigid scaffold from which two hydrophobic groups can project to mimic p53’s Phe19 and Leu26.

Ki of 8.46 mM

IC50 of 86 nM (LNCaP) IC50 of 22,5 nM (PC-3)

MI43 was assumed to closely mimic Leu22 at the two carbon linker between the morpholine ring and the 5’-carbonyl group. The oxygen of the morpholine ring would be in close proximity to the charged amine group in Lys90. This positively charged Lys90 is thought to have a charge-charge interaction to the carbonyl group in p53’s Glu17

MI43 and MI-63 had previously shown great binding affinity however were poor candidates for in vivo evaluation due to their poor PK profile. Extensive modification and in silico simulations led to MI219 as a potent and selective MDM2 inhibitor with a desirable pharmacokinetic profile. Computational binding suggested that MI219 would interact similarly to the key residues in p53, and in vitro screening showed that it binds with a Ki of 5 nM to MDM2 which is >1,000 fold more potent than p53 peptide. It is also seen to be specific to MDM2 over MDMX as it has an IC50 to MDMX of >100 mM and an estimated Ki of 55.7 mM. MI219 is a potent and selective p53/MDM2 inhibitor which induced apoptosis in cancer cells but not in normal cells. showed good oral bioavailability and was therefore investigated in mouse xenograft models of human cancer.

1,4-Benzodiazepine-2,5-diones (BDP)

Johnson and Johnson screened a library of 1,4-benzodiazepine-2,5-diones for binding to the p53 domain of MDM2. Of total, 22K compound were evaluated using a HTS binding assay that measures the affinity of compound toward a MDM2 (residues 17-125). Hits were confirmed using Thermofluor fluorescence polarization assay. It was found that BDPs with a-amino esters as the amine component had a decent activity against p53/MDM2.

Chiral separation afforded two different compounds, typically with drastically different potencies. Substitutions on the phenyl ring showed that a Cl, CF3, or OCF3 showed the greatest increase in activity. Keeping these 3 substituents constant the acid side chain was explored. Aliphatic side chains were found to greatly decrease activity. Compounds containing a parachlorophenyl or parabromophenyl ring afforded compounds with sub micromolar activity; the first of the BDP series. Attempts to replace the iodo group on the benzodiazepine showed only decreases in activity

SAR

Lead compounds of Johnson and Johnson’s benzodiazepine scaffold. It was found that the different diastereomers have drastically different activities

The lead BDP was co crystallized with MDM2 to determine the binding mode of the BDPs. The compound like most other p53/MDM2 inhibitors fits into the Phe19, Trp23, and Leu26 pocket and makes hydrogen bonds to 3 different water molecules but none to MDM2. The interactions to MDM2 are largely nonspecific van der Waals contact. The hydrogen bonds can be removed without substantially affecting the affinity of the molecule to MDM2

The parachlorophenyl group derived from the a-amino ester starting material fits into the Leu26 pocket, the parachlorophenyl group derived from the aldehyde starting material fits into the Trp23 pocket similar to the chlorine containing oxindole (see above), and the iodophenyl moiety binds in the Phe19 pocket

The co-crystallized compound as well as other derivatives were studied in cellular based assays. The activities were dependent on the expression of wild type p53 and MDM2 as determined by lack of potency in mutant or null p53 expressing cell lines or cell lines which no longer express MDM2 and wild type p53

Lead variations of J&J’s benzodiazepine scaffold

This compound was shown to be a potent inhibitor of p53/MDM2 in cellular assays and was improved by the introduction of an ortho amino functionality to the benzylic ring

It is believed to be due to an extra donor hydrogen bond interaction between the amino group and the carbonyl of Val93 on MDM2

However this compound was found to be less potent in cell based assay, most likely due to its zwitterionic characteristic which limits the cross membrane permeability and adversely modulates the availability of the compound to MDM2

Changing the valeric acid side chain with a non-charged side solubilizing group, such as the methoxyethoxyethyl side chain lead to a slight decrease in the FP assay but an increase in the cellular assay indicating that this compound is able to penetrate the cell unlike the second analog. When this group is switched out for a morpholino side chain as a solubilizing group the cellular activity increased even more. However when the orthoamine hydrogen bond donor group was replaced a loss of activity in FP assay and no cellular activity was observed

Dömling et al synthesized and screened compounds from the Ugi-4-componen reaction (1) and the Ugi-4-component-5-centered (U4C5Cr) reaction (2)

1 2

Compounds were screened as racemic mixtures, however co-crystal analysis showed that only one enantiomer was the active form.

The benzyl group mimics the Leu26 of p53, and the tert-butylamide substituent derived from the isocyanide was deeply buried in the Phe19 pocket. As seen previously there was a nice p-p stacking between the 3,4-di-fluoro benzyl amine and His96 of MDM2

It was found that 3,4,5-tri-fluro benzyl amine achieved the greatest binding constant of 130 nM. Cocrystal analysis confirmed the expected binding mode of the 6-chloroindole moiety aligning with the Trp23 of p53, forming a hydrogen bond with Leu54 of MDM2

This compound, as well as another derivative of the

Ugi-4-component reaction show a never before seen pocket open in the MDM2 protein, which extends the ligand-protein interaction site. In addition to their

great protein binding activity these compounds have also shown activity in

Leukemia cells (AML)

Chalcones bind to MDM2 at the p53 transactivation domain binding site

These inhibitors were of low to moderate affinity, with IC50 values in the 50-250 mM range and above. The general low potency of these chalcones possibly reflects a failure of the groups to adequately occupy the hydrophobic pocket. A potential drawback of these a,b-unsaturated ketone derivatives is indiscriminate reaction with cellular nucleophiles including proteins and nucleic acids as Michael acceptors

QSAR study was conducted on a set of high-affinity MDM2 inhibitory peptides using electrostatic and hydrophobic property-based descriptors generated with the HINT program. The pharmacophoric features derived from this set of peptides was subsequently used to formulate a search query that was used to search the NCI chemical database to discover a small molecule pyrazolidinedione sulfonamide derivative lead compound, which represent a promising class of p53/MDM2 binding inhibitors.

the distance restraints were defined with a 20 % tolerance

This compound exhibited moderate affinity, with an IC50 of about 15 mM in competition against peptide binding to MDM2, and was shown to cause an increase in p53 transcriptional activity.

Chalcones boronic acids as inhibitors of p53-MDM2 binding These new chalcones were designed based on the NMR data which indicated that the carboxylic acid group of the chalcones could be placed near the base of Lys51, to form a salt bridge. From the presumption that the acid group of the chalcone forms a salt bridge with this Lys51, and simultaneously breaking the salt bridge it forms with Glut25, it was envisioned that a boronic acid analogue might form a stronger salt bridge with Lys51 than the carboxylic acid analogue.

Norbornane Derivatives

These compounds had hydrophobic groups attached to the norbornane scaffold, and intended to take advantage of the hydrophobic pockets occupied by p53 residues Phe19, Trp23 and Leu26. Among them, five compounds, syc-7, syc-8, syc-11, syc-12 and syc-13 possessed concentration-dependent affinity against MDM2

These compounds showed moderate growth inhibitory activity against MCF-7 (breast), NCI-H446 (small cell lung), HCT-8 (colon) and HeLa (cervical) cancer cell lines, in an MTT assay, at 5 mg/ml, with % inhibition ranging from 50% to 80%

Syc-7 showed about five fold selectivity between MCF7 cells and NEC normal cells, and also stimulated p53 and p21 accumulation, and induced apoptosis

High-affininty binding tryptophan derivatives that can be classified as small molecules were also recently designed to take advantage of the binding locus

of p53’s Trp23 on MDM2

RITA

RITA was purported to bind rather to p53 and disrupt p53-MDM2 binding. It is thought that binding of RITA to p53 changes its conformation at the N-terminal that renders it incapable to binding to MDM2. This compound exhibited strong p53-dependent tumor growth suppression.

In addition to the binding of p53 to MDM2 at the N-terminal domain, other domains of the MDM2 oncoprotein interact with p53

For instance, the RING finger domain of MDM2 interacts with p53 as an E3 ligase to ubiquitinate p53 and target it for proteasomal destruction. Three small molecule compounds, an anilidosulfonamide, a bis-(amidinophenyl)-urea and a benzoylimidazolone can inhibit the E3 ligase activity of MDM2, and antagonize p53 ubiquitination

A series of pyrimido[4,5-b]quinoline-2,4-dione derivatives was synthesized and evaluated for their cytotoxic activities in vitro against five human cancer cell lines. Selected compounds were tested for their MDM2 E3 ligase inhibitory activities and p53-MDM2 binding inhibitory activities. Three compounds showed better p53-MDM2 binding inhibitory potency with IC50 values ranging from 1.3 µM to 9.0 µM.

HLI98C HLI98D HLI98E

Starting with Nutlins as an initial lead, novel bicyclic compounds, aiming to place cis-bischlorophenyl moiety at the equivalent location where the hydrophobic interaction with MDM2 is observed, have recently been developed

R1=iso-pro

In order to discuss the SAR of the thio-benzodiazepine compounds which showed excellent activity against p53–MDM2 PPI, twenty compounds with electrophilic and nucleophilic groups on the benzene ring have been designed and synthesized. Among them, compounds BDP1 (Ki = 91 nM) and BDP2 (Ki = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (Ki = 121 nM). In addition, in vitro antitumor activity against Saos-2, U-2 OS, A549 and NCI-H1299 cell-lines were assayed by the MTT method. Especially, these compounds possessed excellent biological activity and good selectivity comparable to Nutlin-3a, which were promising candidates for further evaluation.

The docking models of thio-benzodiazepines inhibitors with MDM2. The inhibitors are shown in stick models with carbon atoms light purple, nitrogen blue, oxygen red, fluorine light green and sulfur yellow. Hydrogen bonds are depicted as green dashed lines. The amino acid residues which were formatted H-bonds are labeled

BDP1

BDP2

NH

NH

NH

N Serdemetan Phase IJohnson & Johnson

N

N

N

N

462056Biological TestingJanssen

N

N

O

S

N

Lissoclindine BBiological TestingNational Institutes of Health

NCl

O

NO

478102Biological TestingRoche

O

N

N

N


N

NS

N

N

NSC-333003Biological TestingH. Lee Moffitt Center

N

O

N

NSC-66811Biological TestingUniversity of Michigan

N

O

OCl

N N

N SCl

701815Biological TestingPharmaDesign

Cl

N

O

Cl

N


N

N

N

N

O

O


N

O

O

N

N N

S S

F701813Biological TestingPharmaDesign

N

OO

O

Cl

S Cl

475056Biological TestingNexusPharma

N

N

N

N

O


O

N

O

NN

F

O

N


N

N O

O

O

Cl

Cl475057Biological TestingNexusPharma

N

N

O

Cl

ON+

O

O


Representative examples of reported MDM2 small molecule inhibitors

In active MDM2/P53 binding site

MI-63 Preclinical

University of Michigan

3JZK 1T4E

3LBL 1RV1

Examples of crystallographic data obtained for several MDM2 inhibitors

P53/MDM2-targeted library design at CDL involves: • A combined profiling methodology that provides a consensus score and decision based on various advanced in silico tools covering by the top concept of targeted diversity: The following strategy has been applied to design our “First-Step” targeted set: 1. 2D-similarity approach (Tanimoto metric) to the reported inhibitors of p53/MDM2 PPI; 2. Unique isosteric and bioisosteric morphing and funneling procedures in designing novel potential p53/MDM2 inhibitors with high IP value. We apply CDL’s proprietary ChemosoftTM software and commercially available solutions from Accelrys, ChemoSoft, MolSoft, SmartMining, MOE, Daylight and other platforms; 3. Compounds selection based on key structural motifs revealed for reported p53/MDM2 agents; 4. Non-trivial peptidomimetics, including a-helix and b-turn mimetics, which are targeted specifically against PPI within the p53/MDM2 interface (“hot-spot” focus); 5. A particular focus was on Spiro-, sp3-rich and “beyond-flatland” compounds; 6. Topological analogues, e.g. MI-63 skeleton mimetics with crutial binding points and optimal geometry; 7. A subset of high diversity was also included; 8. Analogues of natural-based compounds; 9. ChemDiv’s medchem filters

Concept and Applications

Approaches which are planned to be applied in further design include: 1. Neural Network tools for target-library profiling, in particular Self-organizing Kohonen and Sammon maps, performed in SmartMining Software, Support vector machine (SVM) methodology, etc.; 2. 3D-molecular docking approach; 3. Computational-based `in silico` ADME/Tox assessment for novel compounds includes prediction of human CYP P450-mediated metabolism and toxicity as well as many pharmacokinetic parameters, such as Brain-Blood Barrier (BBB) permeability, Human Intestinal Absorption (HIA), Plasma Protein binding (PPB), Plasma half-life time (T1/2), Volume of distribution in human plasma (Vd), etc. The fundamentals for these applications are described in a series of our recent articles on the design of exploratory small molecule chemistry for bioscreening [for related data visit ChemDiv. Inc. online source: www.chemdiv.com]

Advanced Approaches

1. For the design of our p53/MDM2 PPI we have applied 3D-pharmacophore modeling/searching (see slides below);

• Synthesis, biological evaluation and SAR study for the selected structures: 1. High-throughput synthesis with multiple parallel library validation. Synthetic protocols, building blocks and chemical strategies are available; 2. Library activity validation via bioscreening; SAR is implemented in the next library generation.

http://www.chemdiv.com/





Representative examples of isosteric transformations within MDM2-targeted library

NH

O

Cl

CH3

CH3

CH3

NH

O

NH2

F

Cl

O N

N

NH

NN

O

S

Cl N

N

NH

O

O

N N

O

NH

O

N

S

NH

O

O

Br

N N

NH

O

O

O

N

N

NH

O

O

Br

N

N

O

NH

O

N

NH

O

Cl

Br

Br

1418-0038 6753-0273

8011-8013

4264-2251

3448-5944

8012-1480

D718-0447

8017-2675

S N

NH

O

O

O

O

O

N

NH

O

O

I

N

S

N+

NH

O

O

O

O

NNH

O

O

O

Cl

1683-6928

1699-1169

2280-6602

3771-8118

Representative examples of isosteric transformations within MDM2-targeted library

NH

N

O

COOH

Cl

O

Cl

I

N

N

O

O

O

O

O

N

SN

NH

O

OCl

NNN

O

O

N

N

N

O

O

N

O

O

N

N

N

O

OO

F

N

N

O

N

OCl

0488-0216

F521-0039

M284-0388

F019-3239

0910-0107

E002-1910

N

O

N

O

NN

Cl O

H

N

O

O

H

N O

N

O

O

N

NO

O

O

O

N

N

OO

O

O

C197-0529

C175-0099

C301-3771

Representative examples of ChemDiv compounds with high 2D-structural similarity to the reported

MDM2-related PPI inhibitors O

O Cl

O

OCl

N

ON

O

Cl

S Cl

O

N

SN

O

O

Cl

O

N

O

N N

N

N

O

N

O

O

N

N N

S S

F

N

S

NN

SN

O

O

O

NN

O

O

O

ON

+

O

O

N

N

N+

O

O

O

O

O

O

O

O

Johns Hopkins University 0657-0016

NexusPharma

E456-0569

University of Michigan4896-3730

Inst. Physical Chemical Res.Y020-0449

US Department of Health & Human Services

3871-0142

0.8

0.75

0.74

0.72

0.71

ChemDiv MDM2/p53 3D-Pharmacophore Hypothesis

The superposition of Nutlin 2 (green), MI-63 analog (Yellow), BDP

(purple), Dömling product (grey)

Two similar pharmacophores: 1. Four-centered pharmacophore with one H-bond donor (marked in blue dotted line); 2. Four-centered pharmacophore with one H-bond donor and one H-bond acceptor mapped from BDPs (marked in purple dotted line); 3. Combined pharmacophore: H-bond donor (blue) and H-bond acceptor (purple) ˃ Hydrophobic areas are identical for both pharmacophores developed

Cl

O

OHNH

N

N

Cl

NH

O

Cl

CH3

CH3

CH3

NH

O

NH2

F

Cl

matched compounds (examples) – known MDM2 inhibitors

MI-63

N

N

NS

O

O

O

O

N

N

N

S

O

O

F

ON

N

O

O

O

N

O

ON

F

O

N

N

N S

N

O

O

N

N

N

N OO

N

NN

N

OO

SN

N

NO

O

O

Cl

N

N

N

O

O

ON

N

O

F

C066-0433 C125-0142

C240-0092 G893-0426

K788-5572 L402-0004 L609-2032

P772-0017 L610-0443Y010-0045

Representative examples of compounds successfully passed through the 1st MDM2 pharmacophore model

Representative examples of compounds successfully passed through the 2d MDM2 pharmacophore model

N

N

NS

O

O O

N

N

O

O

F

O

O

NO

O

O

O

N

N N N

SS

O

ON

N SN

O

O

N

NN

O

N

O

N

NO

ON

O

N

N

N

N

O

O

N

N N

ON

O

Cl

NN

N

O

O

O

N

N

S

NN

O

C066-0230 C066-0877 C257-0219

E456-0683 G863-0046

G883-1581

G893-0698

L402-0004

L609-1554 L610-0351

P169-2262

NH

NH

NH

N Serdemetan Phase IJohnson & Johnson

NH

NH

N

NH

462056Biological TestingJanssen O

NH

NH

N


N

NH

NH

N

O

O656352Biological TestingJanssen

N

NH

NH

N

O

CH3


N

OH

NHNH

F

NH

MeO

OMe


Topological pharmacophore for several MDM2 inhibitors

3nd four-centered MDM2 pharmacophore model mapped

from 656352

all the presented compounds are mapped well

Representative examples of compounds successfully passed through the topological pharmacophore

SN

N

O

O

N

O

Cl

O

L718-0017

N

N

SN

N

O

NF

O

P861-0837

N

N

N

O

O

O

O

L610-1001

N

N

O

ON

O

O

O

C066-0932

N

O

N ON

O

O

O

C066-2422

N

N

N

O

O

O

O

M976-0666

N

N

N

ON

O

O

Cl

J065-1058

NN

N

N

N

O

N

P804-0246

NN

S

NO O

C301-6991

NN

N N

N

O O

N

G639-3495

N

N

N

O

N

P323-0693

Key statistical indicators calculated for MDM2-targeted library: - number of compounds: 23K - total diversity coeff.: 0.7851; - number of screens: 5459; - number of unique heterocycles: 381 A wide range of molecular descriptors was calculated for MDM2-targeted library

Here we provide an efficient “first-step” approach for the design of novel MDM2-active compounds. Based on the accumulated knowledgebase, concept of bio- and isosteric morphing, structure diversity and similarity as well as 3D-pharmacophore modeling we have designed MDM2-targeted library of more than 23K small molecule compounds. As a result, the library is renewed each year, proprietary compounds comprising 50-75% of the entire set. Clients are invited to participate in the template selection process prior to launch of our synthetic effort.

Conclusion

Documents

MDM2-Targeted Library