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.
Functional characterization of novel germline TP53 variants in Swedish families.
Kharaziha P, Ceder S, Axell O, Krall M, Fotouhi O, Böhm S, et al
Clin. Genet. 2019 Sep;96(3):216-225
Small molecule activators of the p53 response.
Ladds MJGW, Laín S
J Mol Cell Biol 2019 Jan;():
Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive.
Keszei M, Record J, Kritikou JS, Wurzer H, Geyer C, Thiemann M, et al
J. Clin. Invest. 2018 Aug;128(9):4115-4131
Mass Spectrometry Reveals the Direct Action of a Chemical Chaperone.
Gault J, Lianoudaki D, Kaldmäe M, Kronqvist N, Rising A, Johansson J, et al
J Phys Chem Lett 2018 Jul;9(14):4082-4086
A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
Ladds MJGW, van Leeuwen IMM, Drummond CJ, Chu S, Healy AR, Popova G, et al
Nat Commun 2018 03;9(1):1107
Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib.
Ladds MJGW, Pastor-Fernández A, Popova G, van Leeuwen IMM, Eng KE, Drummond CJ, et al
PLoS ONE 2018 ;13(4):e0195956
Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase.
Costeira-Paulo J, Gault J, Popova G, Ladds MJGW, van Leeuwen IMM, Sarr M, et al
Cell Chem Biol 2018 03;25(3):309-317.e4
cMyc-p53 feedback mechanism regulates the dynamics of T lymphocytes in the immune response.
Madapura HS, Salamon D, Wiman KG, Lain S, Klein E, Nagy N
Cell Cycle 2016 05;15(9):1267-75
Redox effects and cytotoxic profiles of MJ25 and auranofin towards malignant melanoma cells.
Sachweh MC, Stafford WC, Drummond CJ, McCarthy AR, 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 BT, Wagner SA, 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):431-446
Dysregulation of autophagy in chronic lymphocytic leukemia with the small-molecule Sirtuin inhibitor Tenovin-6.
MacCallum SF, Groves MJ, James J, Murray K, Appleyard V, Prescott AR, et al
Sci Rep 2013 ;3():1275
Incompatible effects of p53 and HDAC inhibition on p21 expression and cell cycle progression.
Sachweh MC, Drummond CJ, 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 IM, Higgins M, Campbell J, McCarthy AR, Sachweh MC, Navarro AM, 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 AR, Sachweh MC, Higgins M, Campbell J, Drummond CJ, van Leeuwen IM, 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 HS, Salamon D, Wiman KG, 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 IM, Rao B, Sachweh MC, Laín S
Cell Cycle 2012 May;11(9):1851-61
Synthesis and biological characterisation of sirtuin inhibitors based on the tenovins.
McCarthy AR, Pirrie L, Hollick JJ, 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 IM, Laín S
Oncotarget 2011 Apr;2(4):274-6
Mechanism-specific signatures for small-molecule p53 activators.
van Leeuwen IM, Higgins M, Campbell J, Brown CJ, McCarthy AR, 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 IM, Higgins M, Campbel J, Thompson AM, Lane DP, et al
Oncotarget 2010 Nov;1(7):639-50
Dynamic energy budget approaches for modelling organismal ageing.
van Leeuwen IM, Vera J, Wolkenhauer O
Philos. Trans. R. Soc. Lond., B, Biol. Sci. 2010 Nov;365(1557):3443-54
p53-based cancer therapy.
Lane DP, Cheok CF, Lain S
Cold Spring Harb Perspect Biol 2010 Sep;2(9):a001222
Drug discovery in the p53 field.
Semin. Cancer Biol. 2010 Feb;20(1):1-2
All Publications 1999-2009