Chemical biology approaches to target validation in cancer

doi:10.1016/j.coph.2014.07.007

Current Opinion in Pharmacology

Volume 17, August 2014, Pages 87-100

https://doi.org/10.1016/j.coph.2014.07.007 Get rights and content

Highlights

•
Target validation is especially critical in the context of drugging the cancer genome and clinical drug resistance.
•
We review how chemical biology approaches benefit target validation.
•
We illustrate how critically assessed small molecule chemical inhibitors complement genetic approaches.
•
We highlight recent progress, including reagents for less druggable targets.

Target validation is a crucial element of drug discovery. Especially given the wealth of potential targets emerging from cancer genome sequencing and functional genetic screens, and also considering the time and cost of downstream drug discovery efforts, it is essential to build confidence in a proposed target, ideally using different technical approaches. We argue that complementary biological and chemical biology strategies are essential for robust target validation. We discuss recent progress in the discovery and application of high quality chemical tools and other chemical biology approaches to target validation in cancer. Among other topical examples, we highlight the emergence of designed irreversible chemical tools to study potential target proteins and oncogenic pathways that were hitherto regarded as poorly druggable.

Section snippets

Introduction: setting the scene

Increasing numbers of potential therapeutic targets for cancer are being generated by an exponential growth in genomic information revealing oncogenic driver and dysfunctional tumour-suppressor proteins, coupled with data from other omics analyses, synthetic lethal screens based on RNA interference (RNAi) and classical hypothesis-driven approaches [1, 2, 3, 4, 5••, 6]. Current estimates reveal that approved drugs are available for only 5% of the 500 or so cancer-causing gene products [7^••]. As

Recent examples of the value of complementary chemical and biological validation

Several recent studies reinforce the value of complementary chemical and biological approaches to target validation and in key examples demonstrate how different results may be obtained with orthogonal technical approaches. For example, the kinase TNIK was highlighted in elegant work as an essential activator of WNT target genes [30]. The siRNA-mediated depletion of TNIK and overexpression of mutant TNIK kinase abrogated WNT-dependent transcription, suggesting a likely essential function for

Need for high quality chemical tools

Quality chemical tools provide an ideal opportunity to test the therapeutic hypothesis with an agent close to the profile of the desired highly optimised clinical candidate. In our opinion, demonstration of the desired therapeutic phenotype in cellular and in vivo animal models, in the absence of undesirable toxicity, through the use of multiple fit-for-purpose chemical tools provides the most significant boost to confidence in target validation. Unfortunately, there continue to be frequent

Small molecule chemical tools: reversible target modulation

The value of quality small molecule chemical tools to the bioscience community is particularly highlighted by the enabling work of the Structural Genomics Consortium and their network of industrial and academic collaborators whose mission is to further biological understanding, particularly in the field of epigenetics, through the open provision of high quality chemical probes. This very successful initiative has already spawned a wealth of ground-breaking chemical probes and associated

Small molecule chemical tools: irreversible protein modulation

There has been an emergence of chemical tools, suitable for in vivo use in animals, that selectively bind their target protein via covalent modification. This is an attractive approach, particularly for the modulation of hitherto undruggable protein targets. Key advantages include the ability to completely ablate a specific protein function without removing the protein together with the avoidance of challenging pharmacokinetic (PK) optimisation as a result of essentially irreversible

Concluding remarks

There continues to be a major need to expand the drugged — and chemically probed — cancer genome. Attractive targets are those that represent addictions, vulnerabilities and synthetic lethalities in cancer, including those that are not oncogenes per se, as with the molecular chaperone HSP90. Target space can now be further extended with the emerging new evidence of the powerful therapeutic potential of immune modulation in oncology.

Especially given the explosion of potential drug targets from

Conflict of interest

PW and JB are employees of The Institute of Cancer Research, which has a commercial interest in the discovery and development of a range anticancer drugs and operates a rewards to discoverers scheme. PW is a former employee of AstraZeneca and JB is a former employee and shareholder of Pfizer. The authors declare relevant commercial interactions with Yamanouchi (now Astellas), Piramed Pharma (acquired by Roche), Genentech, Vernalis, Novartis, Chroma Therapeutics, Astex Pharmaceuticals,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

PW and JB are grateful for major core support from Cancer Research [grant number C309/A11566]. PW is a Cancer Research UK Life Fellow [grant number C309/A8992]. The authors acknowledge funding to The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust as a Cancer Research UK Centre and from the National Institute of Health Research to our Biomedical Research Centre. We apologise to the authors of numerous excellent papers that could not be cited because of space constraints.

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View full text

Chemical biology approaches to target validation in cancer

Highlights

Section snippets

Introduction: setting the scene

Recent examples of the value of complementary chemical and biological validation

Need for high quality chemical tools

Small molecule chemical tools: reversible target modulation

Small molecule chemical tools: irreversible protein modulation

Concluding remarks

Conflict of interest

References and recommended reading

Acknowledgements

Chem Biol

J Proteome Res

Methods Enzymol

J Med Chem

ACS Chem Biol

Nat Chem Biol

Angew Chem Int Ed Engl

Nature

J Med Chem

Nat Chem Biol

Signatures of mutational processes in human cancer

Nature

The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups

Nature

Mutational landscape and significance across 12 major cancer types

Nature

Cancer genome landscapes

Science

Drugging cancer genomes

Nat Rev Drug Discov

Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity

Cancer Res

Objective assessment of cancer genes for drug discovery

Nat Rev Drug Discov

The causes and consequences of genetic heterogeneity in cancer evolution

Nature

Clonal evolution in cancer

Nature

Implications of intratumour heterogeneity for treatment stratification

J Pathol

Combinatorial drug therapy for cancer in the post-genomic era

Nat Biotechnol

Identification and validation of protein targets of bioactive small molecules

Bioorg Med Chem

Modern phenotypic drug discovery is a viable, neoclassic pharma strategy

J Med Chem

Application of multiplexed kinase inhibitor beads to study kinome adaptations in drug-resistant leukemia

PLOS ONE

Getting pharmaceutical R&D back on target

Nat Chem Biol

Validating therapeutic targets through human genetics

Nat Rev Drug Discov

Drug development: raise standards for preclinical cancer research

Nature

Believe it or not: how much can we rely on published data on potential drug targets?

Nat Rev Drug Discov

The role of SATB1 in breast cancer pathogenesis

J Natl Cancer Inst

Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

Cell Res

Functional viability profiles of breast cancer

Cancer Discov

Inconsistency in large pharmacogenomic studies

Nature

Policy: NIH plans to enhance reproducibility

Nature

Target validation using chemical probes

Nat Chem Biol

The path to oncology drug target validation: an industry perspective

Methods Mol Biol

Auditing the pharmacological accounts for Hsp90 molecular chaperone inhibitors: unfolding the relationship between pharmacokinetics and pharmacodynamics

Mol Cancer Ther

The kinase TNIK is an essential activator of Wnt target genes

EMBO J

Discovery of 4-phenyl-2-phenylaminopyridine based TNIK inhibitors

Bioorg Med Chem Lett

STK33 kinase activity is nonessential in KRAS-dependent cancer cells

Cancer Res