Antolin, A.A.
Workman, P.
Al-Lazikani, B.
(2021). Public resources for chemical probes: the journey so far and the road ahead. Future medicinal chemistry,
Vol.13
(8),
pp. 731-747.
show abstract
High-quality small molecule chemical probes are extremely valuable for biological research and target validation. However, frequent use of flawed small-molecule inhibitors produces misleading results and diminishes the robustness of biomedical research. Several public resources are available to facilitate assessment and selection of better chemical probes for specific protein targets. Here, we review chemical probe resources, discuss their current strengths and limitations, and make recommendations for further improvements. Expert review resources provide in-depth analysis but currently cover only a limited portion of the liganded proteome. Computational resources encompass more proteins and are regularly updated, but have limitations in data availability and curation. We show how biomedical scientists may use these resources to choose the best available chemical probes for their research..
Mitsopoulos, C.
Micco, P.D.
Villasclaras-Fernández, E.D.
Dolciami, D.
Holt, E.
Mica, I.L.
Coker, E.A.
Tym, J.E.
Campbell, J.
Che, K.H.
Ozer, B.
Kannas, C.C.
Antolin, A.A.
Workman, P.
Al-Lazikani, B.
(2021). canSAR: update to the cancer translational research and drug discovery knowledgebase. Nucleic acids res.,
Vol.49,
pp. D1074-D1082.
Antolin, A.A.
Ameratunga, M.
Banerji, U.
Clarke, P.A.
Workman, P.
Al-Lazikani, B.
(2020). The kinase polypharmacology landscape of clinical PARP inhibitors. Scientific reports,
Vol.10
(1).
show abstract
AbstractPolypharmacology plays an important role in defining response and adverse effects of drugs. For some mechanisms, experimentally mapping polypharmacology is commonplace, although this is typically done within the same protein class. Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet a precise mechanistic rationale to guide clinicians on which to choose for a particular patient is lacking. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. Here, we report the first comprehensive characterization of the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable, submicromolar concentrations. These kinases represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic. Moreover, broad kinome profiling is recommended for the development of PARP inhibitors as PARP-kinase polypharmacology could potentially be exploited to modulate efficacy and side-effect profiles..
Coker, E.A.
Mitsopoulos, C.
Tym, J.E.
Komianou, A.
Kannas, C.C.
Micco, P.D.
Villasclaras-Fernández, E.D.
Ozer, B.
Antolin, A.A.
Workman, P.
Al-Lazikani, B.
(2019). canSAR: update to the cancer translational research and drug discovery knowledgebase. Nucleic acids res.,
Vol.47,
pp. D917-D922.
Antolín, A.A.
Mestres, J.
(2018). Dual Inhibitors of PARPs and ROCKs. Acs omega,
Vol.3
(10),
pp. 12707-12712.
Antolin, A.
Workman, P.
Mestres, J.
Al-Lazikani, B.
(2017). Polypharmacology in Precision Oncology: Current Applications and Future Prospects. Current pharmaceutical design,
Vol.22
(46),
pp. 6935-6945.
Tym, J.E.
Mitsopoulos, C.
Coker, E.A.
Razaz, P.
Schierz, A.C.
Antolin, A.A.
Al-Lazikani, B.
(2016). canSAR: an updated cancer research and drug discovery knowledgebase. Nucleic acids res.,
Vol.44,
pp. 938-943.
Rubio-Perez, C.
Tamborero, D.
Schroeder, M.P.
Antolín, A.A.
Deu-Pons, J.
Perez-Llamas, C.
Mestres, J.
Gonzalez-Perez, A.
Lopez-Bigas, N.
(2015). In Silico Prescription of Anticancer Drugs to Cohorts of 28 Tumor Types Reveals Targeting Opportunities. Cancer cell,
Vol.27
(3),
pp. 382-396.
Antolín, A.A.
Mestres, J.
(2015). Distant Polypharmacology among MLP Chemical Probes. Acs chemical biology,
Vol.10
(2),
pp. 395-400.
Antolín, A.A.
Mestres, J.
(2014). Linking off-target kinase pharmacology to the differential cellular effects observed among PARP inhibitors. Oncotarget,
Vol.5
(10),
pp. 3023-3028.
Antolin, A.A.
Carotti, A.
Nuti, R.
Hakkaya, A.
Camaioni, E.
Mestres, J.
Pellicciari, R.
Macchiarulo, A.
(2013). Exploring the effect of PARP-1 flexibility in docking studies. Journal of molecular graphics and modelling,
Vol.45,
pp. 192-201.
Antolín, A.A.
Jalencas, X.
Yélamos, J.
Mestres, J.
(2012). Identification of Pim Kinases as Novel Targets for PJ34 with Confounding Effects in PARP Biology. Acs chemical biology,
Vol.7
(12),
pp. 1962-1967.
Antolin, A.A.
Tym, J.E.
Komianou, A.
Collins, I.
Workman, P.
Al-Lazikani, B.
Objective, Quantitative, Data-Driven Assessment of Chemical Probes. Cell chemical biology,
.
Sandhu, D.
Antolin, A.A.
Cox, A.R.
Jones, A.M.
Identification of different side effects between PARP inhibitors and their polypharmacological multi‐target rationale. British journal of clinical pharmacology,
.