Assay Detail
Binding
CHEMBL5736134
Review assay metadata, readout intent, target linkage, and publication context from the same page.
fluorescence polarization competition assay (FPCA): Molecular modeling and SILCS functional group affinity mapping (FragMaps) of the Mcl-1 binding site indicated that the carboxylic acid of designed molecule 3a (FIG. 1C) would occupy an energetically favorable region, associated with a salt bridge interaction with R263 of the Mcl-1 binding site, while the ring of the naphthyl core would bind in the p3 pocket demarcated by a favorable non-polar FragMap. The aniline was directed into the hydrophobic p2 pocket, which is also demarcated by a nonpolar FragMap. With the molecular modeling data in hand, compound 3a was then synthesized according to Scheme 1-2.Briefly, commercially available 1-hydroxy-2-naphthoic acid (4) was regioselectively 4-chlorosulfonylated to yield 5, which was isolated by pouring over ice and used without further purification. Sulfonyl chloride 5 was next reacted with 4-bromoaniline to furnish the target molecule 3a in excellent overall yield (83%). Evaluation of 3a in a fluorescence polarization competition assay (FPCA) indicated that it disrupted the Mcl-1-Bak-BH3 PPI with an IC50 of 10.9 μM, corresponding to a Ki of 2.76 μM. Given the ability of 3a to inhibit Mcl-1, a structure-activity relationship (SAR) study was developed, the results of which are presented in the tables below.
336
Total Activities
98
Compounds Tested
3
Activity Types
0
Assay Parameters
Assay Information
| Assay Type | Binding |
| Organism | Homo sapiens |
| Confidence | 9 — Direct single protein target |
| Curated By | Autocuration |
Target
Induced myeloid leukemia cell differentiation protein Mcl-1 (CHEMBL4361) ↗| Type | SINGLE PROTEIN |
| Organism | Homo sapiens |
Publication
Small molecule inhibitors of the MCL-1 oncoprotein and uses thereof
Activity Statistics
| Type | Count | Avg pChEMBL | Best pChEMBL |
|---|---|---|---|
| Ki | 112 | 5.44 | 7.51 |
| kon | 112 | - | - |
| k_off | 112 | - | - |
Compounds Tested
| Compound | Name | Phase | Activities | Best pChEMBL |
|---|---|---|---|---|
| CHEMBL3781822 | — | — | 3 | 7.51 |
| CHEMBL5971523 | — | — | 3 | 7.48 |
| CHEMBL3781669 | — | — | 3 | 7.10 |
| CHEMBL3780803 | — | — | 3 | 7.10 |
| CHEMBL3780225 | — | — | 3 | 7.09 |
| CHEMBL3780311 | — | — | 3 | 6.94 |
| CHEMBL3780473 | — | — | 3 | 6.93 |
| CHEMBL3780719 | — | — | 3 | 6.76 |
| CHEMBL3781894 | — | — | 3 | 6.55 |
| CHEMBL4160782 | — | — | 3 | 6.54 |
| CHEMBL5288359 | — | — | 3 | 6.48 |
| CHEMBL3781396 | — | — | 3 | 6.47 |
| CHEMBL3780113 | — | — | 3 | 6.38 |
| CHEMBL3780576 | — | — | 3 | 6.31 |
| CHEMBL3781019 | — | — | 3 | 6.25 |
| CHEMBL5266385 | — | — | 6 | 6.23 |
| CHEMBL5283389 | — | — | 9 | 6.20 |
| CHEMBL5266814 | — | — | 6 | 6.11 |
| CHEMBL3781946 | — | — | 3 | 5.94 |
| CHEMBL5780908 | — | — | 3 | 5.85 |
| CHEMBL5740477 | — | — | 6 | 5.84 |
| CHEMBL5283550 | — | — | 3 | 5.84 |
| CHEMBL3780617 | — | — | 3 | 5.81 |
| CHEMBL5290264 | — | — | 3 | 5.77 |
| CHEMBL5283049 | — | — | 9 | 5.75 |
| CHEMBL3780990 | — | — | 3 | 5.73 |
| CHEMBL3780290 | — | — | 3 | 5.72 |
| CHEMBL5942219 | — | — | 3 | 5.72 |
| CHEMBL5267976 | — | — | 3 | 5.69 |
| CHEMBL5282573 | — | — | 3 | 5.65 |
Activity Data
| Compound | Name | Type | Rel. | Value | Units | pChEMBL |
|---|---|---|---|---|---|---|
| CHEMBL3781822 | — | Ki | = | 31.0 | nM | 7.51 |
| CHEMBL5971523 | — | Ki | = | 33.0 | nM | 7.48 |
| CHEMBL3781669 | — | Ki | = | 79.0 | nM | 7.10 |
| CHEMBL3780803 | — | Ki | = | 80.0 | nM | 7.10 |
| CHEMBL3780225 | — | Ki | = | 82.0 | nM | 7.09 |
| CHEMBL3780311 | — | Ki | = | 114.0 | nM | 6.94 |
| CHEMBL3780473 | — | Ki | = | 117.0 | nM | 6.93 |
| CHEMBL3780719 | — | Ki | = | 173.0 | nM | 6.76 |
| CHEMBL3781894 | — | Ki | = | 284.0 | nM | 6.55 |
| CHEMBL4160782 | — | Ki | = | 286.0 | nM | 6.54 |
| CHEMBL5288359 | — | Ki | = | 332.0 | nM | 6.48 |
| CHEMBL3781396 | — | Ki | = | 335.0 | nM | 6.47 |
| CHEMBL3780113 | — | Ki | = | 420.0 | nM | 6.38 |
| CHEMBL3780576 | — | Ki | = | 487.0 | nM | 6.31 |
| CHEMBL3781019 | — | Ki | = | 566.0 | nM | 6.25 |
| CHEMBL5266385 | — | Ki | = | 586.0 | nM | 6.23 |
| CHEMBL5266385 | — | Ki | = | 586.0 | nM | 6.23 |
| CHEMBL5283389 | — | Ki | = | 629.0 | nM | 6.20 |
| CHEMBL5283389 | — | Ki | = | 629.0 | nM | 6.20 |
| CHEMBL5283389 | — | Ki | = | 659.0 | nM | 6.18 |
| CHEMBL5266814 | — | Ki | = | 778.0 | nM | 6.11 |
| CHEMBL5266814 | — | Ki | = | 778.0 | nM | 6.11 |
| CHEMBL3781946 | — | Ki | = | 1150.0 | nM | 5.94 |
| CHEMBL5780908 | — | Ki | = | 1400.0 | nM | 5.85 |
| CHEMBL5740477 | — | Ki | = | 1445.0 | nM | 5.84 |
| CHEMBL5283550 | — | Ki | = | 1454.0 | nM | 5.84 |
| CHEMBL3780617 | — | Ki | = | 1540.0 | nM | 5.81 |
| CHEMBL5290264 | — | Ki | = | 1712.0 | nM | 5.77 |
| CHEMBL5283049 | — | Ki | = | 1762.0 | nM | 5.75 |
| CHEMBL5283049 | — | Ki | = | 1762.0 | nM | 5.75 |
| CHEMBL3780990 | — | Ki | = | 1880.0 | nM | 5.73 |
| CHEMBL5942219 | — | Ki | = | 1900.0 | nM | 5.72 |
| CHEMBL3780290 | — | Ki | = | 1910.0 | nM | 5.72 |
| CHEMBL5267976 | — | Ki | = | 2058.0 | nM | 5.69 |
| CHEMBL5282573 | — | Ki | = | 2255.0 | nM | 5.65 |
| CHEMBL3781065 | — | Ki | = | 2500.0 | nM | 5.60 |
| CHEMBL5272237 | — | Ki | = | 2738.0 | nM | 5.56 |
| CHEMBL3781059 | — | Ki | = | 2760.0 | nM | 5.56 |
| CHEMBL5842405 | — | Ki | = | 2940.0 | nM | 5.53 |
| CHEMBL5290076 | — | Ki | = | 2964.0 | nM | 5.53 |
| CHEMBL6047716 | — | Ki | = | 3300.0 | nM | 5.48 |
| CHEMBL3781692 | — | Ki | = | 3860.0 | nM | 5.41 |
| CHEMBL5279726 | — | Ki | = | 4109.0 | nM | 5.39 |
| CHEMBL3781823 | — | Ki | = | 4050.0 | nM | 5.39 |
| CHEMBL5279726 | — | Ki | = | 4109.0 | nM | 5.39 |
| CHEMBL3781264 | — | Ki | = | 4490.0 | nM | 5.35 |
| CHEMBL3781502 | — | Ki | = | 4580.0 | nM | 5.34 |
| CHEMBL3781868 | — | Ki | = | 5030.0 | nM | 5.30 |
| CHEMBL5273839 | — | Ki | = | 5244.0 | nM | 5.28 |
| CHEMBL3780899 | — | Ki | = | 5640.0 | nM | 5.25 |