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Harnessing fluorine–sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs

Harnessing fluorine–sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs
Harnessing fluorine–sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs
Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 ?M, thereby increasing the melting temperature of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small molecule ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine–protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole ethyl anchor, which is deeply buried within the binding site in the Y220C–PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol–1 atom–1). High-resolution crystal structures of the Y220C–ligand complexes combined with quantum chemical calculations revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein–fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells.
1554-8929
2265-2274
Bauer, Matthias R.
606d5d28-6086-4988-89b5-fa07d3619022
Jones, Rhiannon N.
001d0de7-edbd-479c-a243-4e3b61115b0e
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Wilcken, Rainer
54a2bb56-c547-477b-bdda-141de61ca08c
Boeckler, Frank M.
d137746c-22ff-49db-8177-051e246ce7d6
Fersht, Alan R.
b5145a83-e9cb-426f-8722-f60eb9aa59a5
Joerger, Andreas C.
69e42747-d541-4f47-92e5-d8ddd7d73c27
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4
Bauer, Matthias R.
606d5d28-6086-4988-89b5-fa07d3619022
Jones, Rhiannon N.
001d0de7-edbd-479c-a243-4e3b61115b0e
Baud, Matthias
8752d519-3d33-43b6-9a77-ab731d410c2e
Wilcken, Rainer
54a2bb56-c547-477b-bdda-141de61ca08c
Boeckler, Frank M.
d137746c-22ff-49db-8177-051e246ce7d6
Fersht, Alan R.
b5145a83-e9cb-426f-8722-f60eb9aa59a5
Joerger, Andreas C.
69e42747-d541-4f47-92e5-d8ddd7d73c27
Spencer, John
a3cf55cd-a4c7-4af6-b16c-96c8fb8c4cf4

Bauer, Matthias R., Jones, Rhiannon N., Baud, Matthias, Wilcken, Rainer, Boeckler, Frank M., Fersht, Alan R., Joerger, Andreas C. and Spencer, John (2016) Harnessing fluorine–sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs. ACS Chemical Biology, 11 (8), 2265-2274. (doi:10.1021/acschembio.6b00315).

Record type: Article

Abstract

Many oncogenic mutants of the tumor suppressor p53 are conformationally unstable, including the frequently occurring Y220C mutant. We have previously developed several small-molecule stabilizers of this mutant. One of these molecules, PhiKan083, 1-(9-ethyl-9H-carbazole-3-yl)-N-methylmethanamine, binds to a mutation-induced surface crevice with a KD = 150 ?M, thereby increasing the melting temperature of the protein and slowing its rate of aggregation. Incorporation of fluorine atoms into small molecule ligands can substantially improve binding affinity to their protein targets. We have, therefore, harnessed fluorine–protein interactions to improve the affinity of this ligand. Step-wise introduction of fluorines at the carbazole ethyl anchor, which is deeply buried within the binding site in the Y220C–PhiKan083 complex, led to a 5-fold increase in affinity for a 2,2,2-trifluoroethyl anchor (ligand efficiency of 0.3 kcal mol–1 atom–1). High-resolution crystal structures of the Y220C–ligand complexes combined with quantum chemical calculations revealed favorable interactions of the fluorines with protein backbone carbonyl groups (Leu145 and Trp146) and the sulfur of Cys220 at the mutation site. Affinity gains were, however, only achieved upon trifluorination, despite favorable interactions of the mono- and difluorinated anchors with the binding pocket, indicating a trade-off between energetically favorable protein–fluorine interactions and increased desolvation penalties. Taken together, the optimized carbazole scaffold provides a promising starting point for the development of high-affinity ligands to reactivate the tumor suppressor function of the p53 mutant Y220C in cancer cells.

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Accepted/In Press date: 8 June 2016
e-pub ahead of print date: 8 June 2016
Published date: 19 August 2016
Organisations: Chemistry, Faculty of Natural and Environmental Sciences

Identifiers

Local EPrints ID: 400483
URI: https://eprints.soton.ac.uk/id/eprint/400483
ISSN: 1554-8929
PURE UUID: 56267cde-989c-40ca-906d-3569c890589b
ORCID for Matthias Baud: ORCID iD orcid.org/0000-0003-3714-4350

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Date deposited: 16 Sep 2016 14:17
Last modified: 14 Jul 2018 00:28

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Contributors

Author: Matthias R. Bauer
Author: Rhiannon N. Jones
Author: Matthias Baud ORCID iD
Author: Rainer Wilcken
Author: Frank M. Boeckler
Author: Alan R. Fersht
Author: Andreas C. Joerger
Author: John Spencer

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