Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1

James B. Murray; James Davidson; Ijen Chen; Ben Davis; Pawel Dokurno; Christopher J. Graham; Richard Harris; Allan Jordan; Natalia Matassova; Christopher Pedder; Stuart Ray; Stephen D. Roughley; Julia Smith; Claire Walmsley; Yikang Wang; Neil Whitehead; Douglas S. Williamson; Patrick Casara; Thierry Le Diguarher; John Hickman; Jerome Stark; András Kotschy; Olivier Geneste; Roderick E. Hubbard

doi:10.1021/acsomega.9b00611

Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1

James B. Murray, James Davidson, Ijen Chen, Ben Davis, Pawel Dokurno, Christopher J. Graham, Richard Harris, Allan Jordan, Natalia Matassova, Christopher Pedder, Stuart Ray, Stephen D. Roughley, Julia Smith, Claire Walmsley, Yikang Wang, Neil Whitehead, Douglas S. Williamson, Patrick Casara, Thierry Le Diguarher, John HickmanJerome Stark, András Kotschy, Olivier Geneste, Roderick E. Hubbard^*

^*Corresponding author for this work

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using ¹H and ¹⁵N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a K_d of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

Original language	English
Pages (from-to)	8892-8906
Number of pages	15
Journal	ACS Omega
Volume	4
Issue number	5
DOIs	https://doi.org/10.1021/acsomega.9b00611
Publication status	Published - 23 May 2019

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10.1021/acsomega.9b00611

Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl‑2 and Mcl‑1
© 2019 American Chemical Society
Final published version, 4.63 MBLicence: Other

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Murray, J. B., Davidson, J., Chen, I., Davis, B., Dokurno, P., Graham, C. J., Harris, R., Jordan, A., Matassova, N., Pedder, C., Ray, S., Roughley, S. D., Smith, J., Walmsley, C., Wang, Y., Whitehead, N., Williamson, D. S., Casara, P., Le Diguarher, T., ... Hubbard, R. E. (2019). Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1. ACS Omega, 4(5), 8892-8906. https://doi.org/10.1021/acsomega.9b00611

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title = "Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1",

abstract = "We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.",

author = "Murray, {James B.} and James Davidson and Ijen Chen and Ben Davis and Pawel Dokurno and Graham, {Christopher J.} and Richard Harris and Allan Jordan and Natalia Matassova and Christopher Pedder and Stuart Ray and Roughley, {Stephen D.} and Julia Smith and Claire Walmsley and Yikang Wang and Neil Whitehead and Williamson, {Douglas S.} and Patrick Casara and {Le Diguarher}, Thierry and John Hickman and Jerome Stark and Andr{\'a}s Kotschy and Olivier Geneste and Hubbard, {Roderick E.}",

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month = may,

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doi = "10.1021/acsomega.9b00611",

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Murray, JB, Davidson, J, Chen, I, Davis, B, Dokurno, P, Graham, CJ, Harris, R, Jordan, A, Matassova, N, Pedder, C, Ray, S, Roughley, SD, Smith, J, Walmsley, C, Wang, Y, Whitehead, N, Williamson, DS, Casara, P, Le Diguarher, T, Hickman, J, Stark, J, Kotschy, A, Geneste, O & Hubbard, RE 2019, 'Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1', ACS Omega, vol. 4, no. 5, pp. 8892-8906. https://doi.org/10.1021/acsomega.9b00611

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T1 - Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1

AU - Murray, James B.

AU - Davidson, James

AU - Chen, Ijen

AU - Davis, Ben

AU - Dokurno, Pawel

AU - Graham, Christopher J.

AU - Harris, Richard

AU - Jordan, Allan

AU - Matassova, Natalia

AU - Pedder, Christopher

AU - Ray, Stuart

AU - Roughley, Stephen D.

AU - Smith, Julia

AU - Walmsley, Claire

AU - Wang, Yikang

AU - Whitehead, Neil

AU - Williamson, Douglas S.

AU - Casara, Patrick

AU - Le Diguarher, Thierry

AU - Hickman, John

AU - Stark, Jerome

AU - Kotschy, András

AU - Geneste, Olivier

AU - Hubbard, Roderick E.

PY - 2019/5/23

Y1 - 2019/5/23

N2 - We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

AB - We describe our work to establish structure- and fragment-based drug discovery to identify small molecules that inhibit the anti-apoptotic activity of the proteins Mcl-1 and Bcl-2. This identified hit series of compounds, some of which were subsequently optimized to clinical candidates in trials for treating various cancers. Many protein constructs were designed to identify protein with suitable properties for different biophysical assays and structural methods. Fragment screening using ligand-observed NMR experiments identified several series of compounds for each protein. The series were assessed for their potential for subsequent optimization using 1H and 15N heteronuclear single-quantum correlation NMR, surface plasmon resonance, and isothermal titration calorimetry measurements to characterize and validate binding. Crystal structures could not be determined for the early hits, so NMR methods were developed to provide models of compound binding to guide compound optimization. For Mcl-1, a benzodioxane/benzoxazine series was optimized to a Kd of 40 μM before a thienopyrimidine hit series was identified which subsequently led to the lead series from which the clinical candidate S 64315 (MIK 665) was identified. For Bcl-2, the fragment-derived series were difficult to progress, and a compound derived from a published tetrahydroquinone compound was taken forward as the hit from which the clinical candidate (S 55746) was obtained. For both the proteins, the work to establish a portfolio of assays gave confidence for identification of compounds suitable for optimization.

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U2 - 10.1021/acsomega.9b00611

DO - 10.1021/acsomega.9b00611

M3 - Article

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JO - ACS Omega

JF - ACS Omega

IS - 5

ER -

Establishing Drug Discovery and Identification of Hit Series for the Anti-apoptotic Proteins, Bcl-2 and Mcl-1

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