Abstract
Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared with other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1433-1445.e3 |
| Journal | Cell Chemical Biology |
| Volume | 28 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 21 2021 |
| Externally published | Yes |
Keywords
- HSP90
- cancer
- computational
- cross-pharmacology
- drug design
- drug discovery
- kinase
- off-targets
- pharmacology
- polypharmacology
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmacology
- Drug Discovery
- Clinical Biochemistry
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In: Cell Chemical Biology, Vol. 28, No. 10, 21.10.2021, p. 1433-1445.e3.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Evolution of kinase polypharmacology across HSP90 drug discovery
AU - Antolin, Albert A.
AU - Clarke, Paul A.
AU - Collins, Ian
AU - Workman, Paul
AU - Al-Lazikani, Bissan
N1 - Funding Information: A.A.A., P.A.C., I.C., P.W., and B.A.-L. are/were employees of The Institute of Cancer Research (ICR), which has a commercial interest in a range of drug targets, including HSP90 and protein kinases. P.W., P.A.C., and I.C. were involved in the discovery of luminespib, which was funded by Vernalis and Cancer Research UK . The ICR operates a Rewards to Inventors scheme whereby employees of the ICR may receive financial benefit following commercial licensing of a project. P.W. is a consultant/scientific advisory board member for Nextech Invest Ltd , Storm Therapeutics , Astex Pharmaceuticals , Black Diamond , and CV6, and holds stock in Chroma Therapeutics, NextInvest, Black Diamond, and Storm Therapeutics; he is also a non-executive director of Storm Therapeutics and the Royal Marsden NHS Trust; a board member and executive director of the non-profit Chemical Probes Portal; and a former employee of AstraZeneca. P.W. has received research funding from Vernalis, Astex Therapeutics, Merck KGaA, Sixth Element Capital/CRT Pioneer Fund. B.A.-L. is/was a consultant/scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, and Astellas Pharma, and is an ex-employee of Inpharmatica Ltd. A.A.A., B.A.-L., and P.W. have been instrumental in the creation/development of canSAR and Probe Miner. B.A.-L. was instrumental in the creation of ChEMBL and is a director of the non-profit Chemical Probes Portal. I.C. is/was a consultant to Epidarex LLP, AdoRx Therapeutics, and Enterprise Therapeutics, and is a director of the non-profit Chemical Probes Portal. I.C. has received research funding from Astex , Merck KGaA , Janssen Biopharma , Monte Rosa Therapeutics , and Sixth Element Capital/ CRT Pioneer Fund. I.C. holds stock in Monte Rosa Therapeutics AG and is a former employee of Merck Sharp & Dohme. Funding Information: A.A.A. is primarily supported by a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship ( 204735/Z/16/Z ); the People Programme (Marie Curie Actions) of the seventh Framework Program of the European Union ( FP7/2007–2013 ) under REA grant agreement no. 600388 (TECNIOspring program); and the Agency for Business Competitiveness of the Government of Catalonia, ACCIO. B.A.-L., P.C., I.C., and P.W. are funded by a Cancer Research UK (CRUK) program grant to the CRUK Cancer Therapeutics Unit (grant C309/A11566 ). B.A.-L. and P.W. are funded by a Wellcome Trust biomedical resource and technology grant to sustain and develop the Chemical Probes Portal ( 212969/Z/18/Z ) and a CRUK Drug Discovery Committee strategic award to sustain and develop canSAR ( C35696/A23187 ). P.W. is a CRUK Life Fellow and is funded by the Chordoma Foundation and Mark Foundation . P.W. and B.A.-L. are members of the CRUK ICR/ Imperial Convergence Science Centre ( A26234 ). We acknowledge infrastructure support from CRUK for the ICR CRUK Centre and NHS funding to the NIHR Biomedical Research Center at the ICR and Royal Marsden NHS Foundation Trust . The authors thank many colleagues and collaborators for helpful discussions and valuable input into the preparation of this manuscript. In particular, the authors thank Udai Banerji for valuable discussions and advice. Funding Information: A.A.A. is primarily supported by a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship (204735/Z/16/Z); the People Programme (Marie Curie Actions) of the seventh Framework Program of the European Union (FP7/2007?2013) under REA grant agreement no. 600388 (TECNIOspring program); and the Agency for Business Competitiveness of the Government of Catalonia, ACCIO. B.A.-L. P.C. I.C. and P.W. are funded by a Cancer Research UK (CRUK) program grant to the CRUK Cancer Therapeutics Unit (grant C309/A11566). B.A.-L. and P.W. are funded by a Wellcome Trust biomedical resource and technology grant to sustain and develop the Chemical Probes Portal (212969/Z/18/Z) and a CRUK Drug Discovery Committee strategic award to sustain and develop canSAR (C35696/A23187). P.W. is a CRUK Life Fellow and is funded by the Chordoma Foundation and Mark Foundation. P.W. and B.A.-L. are members of the CRUK ICR/Imperial Convergence Science Centre (A26234). We acknowledge infrastructure support from CRUK for the ICR CRUK Centre and NHS funding to the NIHR Biomedical Research Center at the ICR and Royal Marsden NHS Foundation Trust. The authors thank many colleagues and collaborators for helpful discussions and valuable input into the preparation of this manuscript. In particular, the authors thank Udai Banerji for valuable discussions and advice. A.A.A. P.A.C. P.W. and B.A.-L. designed the research. A.A.A. performed the computational research and managed the experimental work. A.A.A. P.A.C. I.C. P.W. and B.A.-L. conducted data analysis and interpretation. A.A.A. P.A.C. I.C. P.W. and B.A.-L. contributed to manuscript preparation. A.A.A. P.A.C. I.C. P.W. and B.A.-L. are/were employees of The Institute of Cancer Research (ICR), which has a commercial interest in a range of drug targets, including HSP90 and protein kinases. P.W. P.A.C. and I.C. were involved in the discovery of luminespib, which was funded by Vernalis and Cancer Research UK. The ICR operates a Rewards to Inventors scheme whereby employees of the ICR may receive financial benefit following commercial licensing of a project. P.W. is a consultant/scientific advisory board member for Nextech Invest Ltd, Storm Therapeutics, Astex Pharmaceuticals, Black Diamond, and CV6, and holds stock in Chroma Therapeutics, NextInvest, Black Diamond, and Storm Therapeutics; he is also a non-executive director of Storm Therapeutics and the Royal Marsden NHS Trust; a board member and executive director of the non-profit Chemical Probes Portal; and a former employee of AstraZeneca. P.W. has received research funding from Vernalis, Astex Therapeutics, Merck KGaA, Sixth Element Capital/CRT Pioneer Fund. B.A.-L. is/was a consultant/scientific advisory board member for GSK, Open Targets, Astex Pharmaceuticals, and Astellas Pharma, and is an ex-employee of Inpharmatica Ltd. A.A.A. B.A.-L. and P.W. have been instrumental in the creation/development of canSAR and Probe Miner. B.A.-L. was instrumental in the creation of ChEMBL and is a director of the non-profit Chemical Probes Portal. I.C. is/was a consultant to Epidarex LLP, AdoRx Therapeutics, and Enterprise Therapeutics, and is a director of the non-profit Chemical Probes Portal. I.C. has received research funding from Astex, Merck KGaA, Janssen Biopharma, Monte Rosa Therapeutics, and Sixth Element Capital/CRT Pioneer Fund. I.C. holds stock in Monte Rosa Therapeutics AG and is a former employee of Merck Sharp & Dohme. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Publisher Copyright: © 2021 The Authors
PY - 2021/10/21
Y1 - 2021/10/21
N2 - Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared with other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.
AB - Most small molecules interact with several target proteins but this polypharmacology is seldom comprehensively investigated or explicitly exploited during drug discovery. Here, we use computational and experimental methods to identify and systematically characterize the kinase cross-pharmacology of representative HSP90 inhibitors. We demonstrate that the resorcinol clinical candidates ganetespib and, to a lesser extent, luminespib, display unique off-target kinase pharmacology as compared with other HSP90 inhibitors. We also demonstrate that polypharmacology evolved during the optimization to discover luminespib and that the hit, leads, and clinical candidate all have different polypharmacological profiles. We therefore recommend the computational and experimental characterization of polypharmacology earlier in drug discovery projects to unlock new multi-target drug design opportunities.
KW - HSP90
KW - cancer
KW - computational
KW - cross-pharmacology
KW - drug design
KW - drug discovery
KW - kinase
KW - off-targets
KW - pharmacology
KW - polypharmacology
UR - http://www.scopus.com/inward/record.url?scp=85117349374&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117349374&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2021.05.004
DO - 10.1016/j.chembiol.2021.05.004
M3 - Article
C2 - 34077750
AN - SCOPUS:85117349374
SN - 2451-9456
VL - 28
SP - 1433-1445.e3
JO - Cell Chemical Biology
JF - Cell Chemical Biology
IS - 10
ER -