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Exploring the Scaffold Universe of Kinase Inhibitors Ye Hu, and Jürgen Bajorath J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/jm501237k • Publication Date (Web): 05 Sep 2014 Downloaded from http://pubs.acs.org on September 8, 2014
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Journal of Medicinal Chemistry
Exploring the Scaffold Universe of Kinase Inhibitors
Ye Hu and Jürgen Bajorath*
Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113 Bonn, Germany.
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Abstract
The scaffold concept was applied to systematically determine, analyze, and compare core structures of kinase inhibitors. From publicly available inhibitors of the human kinome, scaffolds and cyclic skeletons were systematically extracted and organized taking activity data, structural relationships, and retrosynthetic criteria into account. Scaffold coverage varied greatly across the kinome, and many scaffolds representing compounds with different activity profiles were identified. The majority of kinase inhibitor scaffolds were involved in welldefined yet distinct structural relationships, which had different consequences on compound activity. Scaffolds exclusively representing highly potent compounds were identified as well as structurally analogous scaffolds with very different degrees of promiscuity. Scaffold relationships presented herein suggest a variety of hypotheses for inhibitor design. Our detailed organization of the kinase inhibitor scaffold universe with respect to different activity and structural criteria, all scaffolds, and the original compound data assembled for our analysis are made freely available.
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Journal of Medicinal Chemistry
Introduction
For nearly three decades, the search for ‘privileged substructures’1 or ‘masterkeys’2 has been a major topic in medicinal chemistry to aid in the design of compounds that preferentially interact with members of a given target family. Such privileged structural motifs, if they can be identified, are typically considered as core structure templates for compound generation.2 Core structures are represented using molecular scaffolds,3 another popular concept in medicinal chemistry. Molecular scaffolds can be derived in different ways,3 for example, by calculating the maximum common core structure of a series of compounds,3 by applying retrosynthetic reaction rules,4 or by removal of R-groups from compounds (for which different rules might be applied).5 From a medicinal chemistry perspective, each scaffold definition has pros and cons for core structure representation and no single scaffold definition has become a generally applied standard. In fact, the term scaffold is often rather loosely used in the literature, often without clear definitions.3 This might be acceptable when individual compounds or small series are investigated but for a systematic determination and analysis of scaffolds, the consistent application of clear scaffold definitions is essential. The probably most widely used scaffold definition follows a molecular hierarchy and extracts scaffolds from compounds by removal of all ‘side chain’ substituents while retaining all ring systems and linkers between them.5 From such hierarchically derived scaffolds, one can further abstract by converting all heteroatoms to carbon and setting all bond orders to one, thus generating so-called ‘cyclic skeletons’,6 which represent subsets of topologically equivalent scaffolds. The hierarchical scaffold definition has the advantage of representing a generally applicable and consistent methodological framework for the generation of molecular scaffolds from essentially all classes of ring-containing compounds, but also has some potential limitations.3 For example, the addition of a ring to a scaffold always defines a new scaffold, although ring additions are often carried out during analog design. Hence, ACS Paragon Plus Environment
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hierarchical scaffolds might separate analog series into subseries characterized by differences in ring or linker content, which might increase the complexity of core structure analysis, at least for combinatorial chemistry efforts. Nonetheless, hierarchical scaffolds typically provide a reasonable and chemically interpretable representation of molecular cores. Protein kinases are among the most intensely investigated targets for a variety of therapeutic applications.7,8 Accordingly, a wealth of kinase inhibitors have been reported over the past one or two decades. Most of the currently available inhibitors target the ATP cofactor binding site in kinases.9,10 Given the large numbers of kinase inhibitors that have become available in recent years, we have carried out a comprehensive analysis of inhibitor scaffolds, taking kinase target classification, structural relationships among scaffolds, and kinase inhibitor promiscuity into account. The results of our analysis provide an unprecedentedly detailed classification of systematically derived kinase inhibitor scaffolds. Many sets of scaffolds with different medicinal chemistry relevant characteristics have been generated, providing a wealth of differentiated scaffold information. The entire classification and all structural data are made freely available to the scientific community to provide a basis for further analysis and the exploration of core structures and privileged structural motifs for the development of kinase inhibitors.
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Journal of Medicinal Chemistry
Materials and Methods
Compound activity data From ChEMBL11 release 18, compounds with reported direct interactions (i.e., target relationship type “D”) with human kinase targets at the highest confidence level (i.e., target confidence score 9) were extracted. ChEMBL represents the currently most comprehensive pubic repository of compound data from medicinal chemistry sources and includes information from other databases.11 Two different types of potency measurements were separately considered including (assay-independent) equilibrium constants (i.e., Ki values) and (assay-dependent) IC50 values. Only inhibitors with explicitly defined Ki or IC50 values were considered to ensure a high level of data integrity. Approximate measurements such as “>”, “1000 1000
500
100
50
20
10
5
3
1
5 10 # Kinases
20 1
2-4
≥5
1
388
135
9
2-10
133
60
10
> 10
6
17
3
30 50
# Compounds
>50 1
2 3 4 5 10 # Kinases (promiscuity)
>10
(b) IC50 subset 1 # BM scaffolds 2
# Compounds
4
>1000 1000
500
100
50
20
10
5
3
1
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5 10 # Kinases
20 1
2-4
≥5
1
4015
1019
100
2-10
1264
558
107
> 10
136
96
48
30 50
# Compounds
>50 1
2 3 4 5 10 # Kinases (promiscuity)
>10
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Figure 15
18 compounds | 30 kinases
3|1
4|1
4|1
2|2
24 | 3
5|3
5|4
36 | 14
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Figure 16
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Table 1. Kinase inhibitor data sets.
Number of
Ki
IC50
Inhibitors
1760
17,775
Kinases
94
264
Interactions
2654
25,043
BM scaffolds
761
7343
CSKs
442
3503
For the Ki- and IC50-based kinase inhibitor subsets, the number of kinase inhibitors, kinases these inhibitors were active against, and kinase-inhibitor interactions is reported. In addition, the number of Bemis-Murcko (BM) scaffolds and cyclic skeletons (CSKs) extracted from all kinase inhibitors is given.
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Table 2. Promiscuity of structurally related scaffolds.
# Scaffold pairs (structural relationships) Difference in promiscuity (∆promiscuity)
At least one scaffold with ≥ 2 compounds
Total
Both scaffolds with ≥ 2 compounds
Ki
IC50
Ki
IC50
Ki
IC50
0
1920
25,285
1056
13,581
233
3020
1
347
6957
233
4902
59
1323
2
113
2632
101
2063
37
619
3
76
1849
57
1535
13
483
4
33
965
33
813
14
271
5
4
858
4
766
1
252
6
4
373
4
361
0
139
7
-
403
-
399
-
142
8
14
310
3
300
0
91
9
-
108
-
101
-
31
10
-
85
-
83
-
32
11 – 20
-
463
-
417
-
126
> 20
-
71
-
57
-
22
For the Ki- and IC50-based subsets, the number of scaffold pairs forming structural relationships with increasingly large differences in promiscuity rates is reported. In addition, the number of scaffold pairs is reported in which at least one scaffold or both scaffolds represented multiple compounds.
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Table 3. Scaffold-based RECAP-MMPs.
Number of
Ki
IC50
RECAP-MMPs
770
8945
Scaffolds forming RECAP-MMPs
404 (53.1%)
4354 (59.3%)
Same or overlap
766
8348
Distinct
4
597
MMPs, CSK equivalences or substructure relationships
770
8942
None
0
3
Activity comparison
Structural relationships
For the Ki- and IC50-based subsets, the number of scaffold pairs forming transformation sizerestricted RECAP-MMPs is reported. The number (and ratio) of scaffolds involved in the formation of these retrosynthetic MMPs is given. Furthermore, the number of RECAP-MMPs formed by scaffolds with the same or overlapping kinase activity and with distinct activity is reported. In addition, the number of RECAP-MMPs that were also involved in other structural relationships is provided.
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Table 4. Promiscuity of synthetically related scaffolds.
# RECAP-MMPs Difference in promiscuity (∆promiscuity)
At least one scaffold with ≥ 2 compounds
Total
Both scaffolds with ≥ 2 compounds
Ki
IC50
Ki
IC50
Ki
IC50
0
640
6825
351
3426
89
776
1
91
1080
60
742
9
184
2
23
398
21
310
6
76
3
11
171
10
134
2
36
4
4
110
4
86
1
27
5
1
81
1
70
1
14
6
-
48
-
47
-
14
7
-
56
-
53
-
16
8
-
65
-
63
-
8
9
-
19
-
17
-
4
10
-
16
-
16
-
4
11 – 20
-
58
-
49
-
14
> 20
-
18
-
10
-
4
For the Ki- and IC50-based subsets, the number of RECAP-MMPs formed by scaffold pairs with increasingly large differences in promiscuity is reported. In addition, the number of RECAP-MMPs is given in which at least one scaffold or both scaffolds represented multiple compounds.
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Table of Contents Graphic
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