Design and Synthesis of Novel Aminoindazole-pyrrolo[2,3-b]pyridine Inhibitors of IKKα That Selectively Perturb Cellular Non-Canonical NF-κB Signalling
Abstract
:1. Introduction
2. Results and Discussion
2.1. Inhibitor Design and Structure–Activity Relationship
2.2. Chemistry
2.3. Physicochemical/DMPK Analysis
2.4. Kinome Profiling
2.5. Cell-Based Assessment
2.6. Conclusions
3. Materials and Methods
3.1. Docking
3.2. Chemistry
3.3. Assessment of Kinase Activity of IKKα and IKKβ In Vitro
3.4. In Vitro DMPK Studies
3.5. Cell-Based Studies
3.5.1. Materials
3.5.2. Methodology
Cell Culture
Treatment of Cells, Preparation of Samples, and Western Blotting
Data Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Ki Values (nM) | |
---|---|---|
IKKα | IKKβ | |
2 | 2 | 77 |
3 | 3 | 5 |
4 | 3 | 15 |
Cmpd | R1 | R2 | R3 | R4 | Ki Values (nM) | |
---|---|---|---|---|---|---|
IKKα | IKKβ | |||||
5a | OH | H | H | H | 4 | 42 |
5b | OEt | H | H | H | 8 | 86 |
5c | H | NH2 | H | H | 5 | 28 |
5d | H | OH | H | H | 5 | 26 |
5e | H | OMe | H | H | 5 | 40 |
5f | H | OH | H | F | 4 | 42 |
5g | H | OMe | H | F | 3 | 32 |
5h | H | H | H | 8 | 168 | |
5i | H | H | H | 5 | 159 | |
5j | H | H | H | 3 | 109 | |
5k | H | H | H | 3 | 36 | |
5l | H | H | H | 6 | 25 | |
5m | H | H | H | 15 | 107 | |
5n | H | H | H | 10 | 191 | |
5o | H | H | H | 19 | 458 | |
5p | H | H | H | 35 | 470 | |
5q | OBn | H | H | H | 57 | 1064 |
5r [SU1261] | H | H | H | 10 | 680 | |
5s | H | H | OBn | H | 16 | 189 |
5t | H | NHTs | H | H | 10 | 1048 |
5u | H | H | NHTs | H | 4 | 67 |
5v | H | H | H | 24 | 215 | |
5w | H | H | H | 16 | 402 | |
5x | H | H | H | 8 | 122 | |
5y | H | H | H | 9 | 29 | |
5z | H | H | H | 43 | 166 | |
5aa | H | H | H | 25 | 149 |
Cmpd | R | Ki Values (nM) | |
---|---|---|---|
IKKα | IKKβ | ||
6a | 59 | 5029 | |
6b | 29 | 1215 | |
6c | 26 | 1532 | |
6d | 12 | 22 | |
6e | 21 | 1550 | |
6f | 33 | 503 | |
6g [SU1349] | 16 | 3352 | |
6h | 5 | 1180 | |
6i | 127 | 3000 | |
6j | 25 | 2300 | |
6k | 6 | 12 | |
6l | 42 | 1600 |
Cmpd | Solubility (μM) | Mouse Hepatocyte Clearance (μL/min/106 Cells) | Mouse Hepatocyte Half-Life (min) |
---|---|---|---|
5r [SU1261] | <1 | 38 | 36 |
6b | 3.75 | N.D. | N.D. |
6c | 2 | N.D. | N.D. |
6e | 6.5 | N.D. | N.D. |
6f | 3.75 | N.D. | N.D. |
6g [SU1349] | 20 | 27 | 51 |
6h | 2 | N.D. | N.D. |
6j | 2 | N.D. | N.D. |
6k | >100 | 11 | 121 |
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Riley, C.; Ammar, U.; Alsfouk, A.; Anthony, N.G.; Baiget, J.; Berretta, G.; Breen, D.; Huggan, J.; Lawson, C.; McIntosh, K.; et al. Design and Synthesis of Novel Aminoindazole-pyrrolo[2,3-b]pyridine Inhibitors of IKKα That Selectively Perturb Cellular Non-Canonical NF-κB Signalling. Molecules 2024, 29, 3515. https://doi.org/10.3390/molecules29153515
Riley C, Ammar U, Alsfouk A, Anthony NG, Baiget J, Berretta G, Breen D, Huggan J, Lawson C, McIntosh K, et al. Design and Synthesis of Novel Aminoindazole-pyrrolo[2,3-b]pyridine Inhibitors of IKKα That Selectively Perturb Cellular Non-Canonical NF-κB Signalling. Molecules. 2024; 29(15):3515. https://doi.org/10.3390/molecules29153515
Chicago/Turabian StyleRiley, Christopher, Usama Ammar, Aisha Alsfouk, Nahoum G. Anthony, Jessica Baiget, Giacomo Berretta, David Breen, Judith Huggan, Christopher Lawson, Kathryn McIntosh, and et al. 2024. "Design and Synthesis of Novel Aminoindazole-pyrrolo[2,3-b]pyridine Inhibitors of IKKα That Selectively Perturb Cellular Non-Canonical NF-κB Signalling" Molecules 29, no. 15: 3515. https://doi.org/10.3390/molecules29153515