Sonia Lain Group

Discovery and elucidation of the mechanisms of action of tumour selective compounds

Conventional chemotherapeutics show little selectivity for cancer cells and therefore cause undesired side effects on normal tissues. Furthermore, because conventional anticancer drugs are either DNA-damaging or mitotic poisons, they cause mutations and genomic instability. In the long term, this genotoxicity raises the risk of relapse due to drug resistance acquisition as well as second tumour appearance later in life. This, together with the fact that there are still a significant number of cancers that do not respond to classic therapy implies that there is a great need for new and safer anticancer agents.

In order to identify new cancer therapeutics we follow the strategy described below

  • First we screen for compounds that activate the tumour suppressor protein p53 in a cancer cell line of choice where p53 is not mutated.
  • We then select those compounds that increase p53 activity in cancer cells but not (or at least weakly) in non-cancerous cells.
  • These compounds are tried for their ability to kill tumour cells and normal cells and those that show the best indications of potentially having a wide therapeutic window are tested for genotoxicity and used in preclinical murine models or in blood samples from leukaemia patients.
  • In the next step, which is the most challenging part of our approach, we identify the target(s) for the compounds and use this information to optimise our moleclules further.

Whether the compounds target p53 directly, or whether p53 activation is an important event to achieve selective tumour cell death is of no significance in our approach. The reason we look for p53 activators is the wide range of available reagents to study p53 regulation. This allows us to rapidly test a hypothesis on the mechanism of action for a given compound.

Over the last five years we have proven that this is indeed the case. We have identified mechanisms of action and direct targets in cells for more than forty compounds. Identifying targets for small molecules in cells is very important not only to optimize molecules, but also to select cancer types that are most likely to be responsive.

Group Members


Sonia Lain

Phone: +46-(0)8-524 846 03
Organizational unit: Sonia Lain group

PhD student

Marcus Ladds

Organizational unit: Sonia Lain group

Senior research specialist

Ingeborg van Leeuwen

Phone: +46-(0)8-524 872 19
Organizational unit: Sonia Lain group

Graduate Student

Gergana Popova

Organizational unit: Sonia Lain group


Paul Drescher

Organizational unit: Sonia Lain group


cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response.
Madapura H, Salamon D, Wiman K, Lain S, Klein E, Nagy N
Cell Cycle 2016 May;15(9):1267-75

Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells.
Sachweh M, Stafford W, Drummond C, McCarthy A, Higgins M, Campbell J, et al
Oncotarget 2015 Jun;6(18):16488-506

Acetylation site specificities of lysine deacetylase inhibitors in human cells.
Schölz C, Weinert B, Wagner S, Beli P, Miyake Y, Qi J, et al
Nat. Biotechnol. 2015 Apr;33(4):415-23

SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth.
Ma L, Maruwge W, Strambi A, D'Arcy P, Pellegrini P, Kis L, et al
Cell Death Dis 2014 Oct;5():e1483

SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells.
Li L, Osdal T, Ho Y, Chun S, McDonald T, Agarwal P, et al
Cell Stem Cell 2014 Oct;15(4):431-46

Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6.
MacCallum S, Groves M, James J, Murray K, Appleyard V, Prescott A, et al
Sci Rep 2013 ;3():1275

Incompatible effects of p53 and HDAC inhibition on p21 expression and cell cycle progression.
Sachweh M, Drummond C, Higgins M, Campbell J, Laín S
Cell Death Dis 2013 Mar;4():e533

Modulation of p53 C-terminal acetylation by mdm2, p14ARF, and cytoplasmic SirT2.
van Leeuwen I, Higgins M, Campbell J, McCarthy A, Sachweh M, Navarro A, et al
Mol. Cancer Ther. 2013 Apr;12(4):471-80

Tenovin-D3, a novel small-molecule inhibitor of sirtuin SirT2, increases p21 (CDKN1A) expression in a p53-independent manner.
McCarthy A, Sachweh M, Higgins M, Campbell J, Drummond C, van Leeuwen I, et al
Mol. Cancer Ther. 2013 Apr;12(4):352-60

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP.
Madapura H, Salamon D, Wiman K, Lain S, Klein G, Klein E, et al
Cell Cycle 2012 Dec;11(24):4563-9

An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells.
van Leeuwen I, Rao B, Sachweh M, Laín S
Cell Cycle 2012 May;11(9):1851-61

Synthesis and biological characterisation of sirtuin inhibitors based on the tenovins.
McCarthy A, Pirrie L, Hollick J, Ronseaux S, Campbell J, Higgins M, et al
Bioorg. Med. Chem. 2012 Mar;20(5):1779-93

Pharmacological manipulation of the cell cycle and metabolism to protect normal tissues against conventional anticancer drugs.
van Leeuwen I, Laín S
Oncotarget 2011 Apr;2(4):274-6

Mechanism-specific signatures for small-molecule p53 activators.
van Leeuwen I, Higgins M, Campbell J, Brown C, McCarthy A, Pirrie L, et al
Cell Cycle 2011 May;10(10):1590-8

Evaluation of an Actinomycin D/VX-680 aurora kinase inhibitor combination in p53-based cyclotherapy.
Rao B, van Leeuwen I, Higgins M, Campbel J, Thompson A, Lane D, et al
Oncotarget 2010 Nov;1(7):639-50

Dynamic energy budget approaches for modelling organismal ageing.
van Leeuwen I, Vera J, Wolkenhauer O
Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2010 Nov;365(1557):3443-54

p53-based cancer therapy.
Lane D, Cheok C, Lain S
Cold Spring Harb Perspect Biol 2010 Sep;2(9):a001222

Drug discovery in the p53 field.
Lain S
Semin. Cancer Biol. 2010 Feb;20(1):1-2

Awakening guardian angels: drugging the p53 pathway.
Brown C, Lain S, Verma C, Fersht A, Lane D
Nat. Rev. Cancer 2009 Dec;9(12):862-73

Leptomycin B induces apoptosis in cells containing the whole HPV 16 genome.
Jolly C, Gray L, Parish J, Lain S, Herrington C
Int. J. Oncol. 2009 Sep;35(3):649-56

SysBioMed report: advancing systems biology for medical applications.
Wolkenhauer O, Fell D, De Meyts P, Blüthgen N, Herzel H, Le Novère N, et al
IET Syst Biol 2009 May;3(3):131-6

Ribosomal protein S3: A multi-functional protein that interacts with both p53 and MDM2 through its KH domain.
Yadavilli S, Mayo L, Higgins M, Lain S, Hegde V, Deutsch W
DNA Repair (Amst.) 2009 Oct;8(10):1215-24

Novel cambinol analogs as sirtuin inhibitors: synthesis, biological evaluation, and rationalization of activity.
Medda F, Russell R, Higgins M, McCarthy A, Campbell J, Slawin A, et al
J. Med. Chem. 2009 May;52(9):2673-82

Sirtuins and p53.
van Leeuwen I, Lain S
Adv. Cancer Res. 2009 ;102():171-95

An integrative computational model for intestinal tissue renewal.
van Leeuwen I, Mirams G, Walter A, Fletcher A, Murray P, Osborne J, et al
Cell Prolif. 2009 Oct;42(5):617-36

Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator.
Lain S, Hollick J, Campbell J, Staples O, Higgins M, Aoubala M, et al
Cancer Cell 2008 May;13(5):454-63

Characterization, chemical optimization and anti-tumour activity of a tubulin poison identified by a p53-based phenotypic screen.
Staples O, Hollick J, Campbell J, Higgins M, McCarthy A, Appleyard V, et al
Cell Cycle 2008 Nov;7(21):3417-27

p53 as a therapeutic target.
Staples O, Steele R, Lain S
Surgeon 2008 Aug;6(4):240-3

Selective induction of apoptosis by leptomycin B in keratinocytes expressing HPV oncogenes.
Gray L, Bjelogrlic P, Appleyard V, Thompson A, Jolly C, Lain S, et al
Int. J. Cancer 2007 Jun;120(11):2317-24

Elucidating the interactions between the adhesive and transcriptional functions of beta-catenin in normal and cancerous cells.
van Leeuwen I, Byrne H, Jensen O, King J
J. Theor. Biol. 2007 Jul;247(1):77-102

Towards a multiscale model of colorectal cancer.
van Leeuwen I, Edwards C, Ilyas M, Byrne H
World J. Gastroenterol. 2007 Mar;13(9):1399-407

All Publications 1999-2009

Publications 1999-2009 (Pdf file, 129 Kb)

Tumour Biology