Discovery and Development of Cancer Drugs Acting on New Molecular Targets

Signal Transduction and Molecular Pharmacology Team

Section: Cancer Research UK Cancer Therapeutics Unit

There is now overwhelming evidence that cancer is caused by the mutation and altered expression of genes, leading to the various hallmarks of malignancy. This has led to a new paradigm for the discovery and development of novel cancer drugs that act on molecular targets that are deregulated in oncogenesis. Of particular interest to us is that the hijacking of signal transduction pathways during oncogenesis leads to a greater dependence of cancer cells, when compared to healthy counterparts, on the signalling pathways exploited by cancer genes – a phenomenon known as ‘oncogene addiction’. This forms the basis of therapeutic selectivity for cancer versus normal cells and the prospects of developing drugs that are much more effective and have fewer side effects than the previous generation of cytotoxic agents.

We now have the exciting potential to move to truly personalised cancer medicine, in which patients are treated with drugs that are precisely tailored to the molecular pathology of the individual cancer. This requires not only new drugs acting on multiple key targets that lie on all of the key oncogenic pathways but also biomarkers than can identify patients best suited to a particular treatment.

With this new paradigm, the Cancer Research UK Centre for Cancer Therapeutics is actively involved in the discovery and development of a wide range of drugs. The Signal Transduction and Molecular Pharmacology Team is involved in many of these projects and is particularly interested in inhibitors of the molecular chaperone Heat Shock Protein 90 (HSP90), PI3 kinase and chromatin-modifying enzymes. We apply a range of powerful technologies to help validate drug targets and to study the mechanism of action and molecular pharmacology of agents that are under development. These include RNA interference and gene expression profiling.

References

Workman P. Drugging the cancer kinome: progress and challenges in developing personalized molecular cancer therapeutics. Cold Spring Harb Symp Quant Biol 70: 499-515, 2005

Workman P; Clarke PA; Guillard S; Raynaud FI. Drugging the PI3 kinome. Nat Biotechnol 24: 794-796, 2006

Sharp S; Workman P. Inhibitors of HSP90 molecular chaperone: Current status. Adv Cancer Res 95: 323-348, 2006

McDonald E; Jones K; Brough PA; Drysdale MJ; Workman P. Discovery and development of pyrazole-scaffold HSP90 inhibitors. Curr Top Med Chem 6: 1193-1203, 2006

Hayakawa M; Kaizawa H; Moritomo H; Koizumi T; Ohishi T; Okada M; Ohta M; Tsukamoto SI; Parker P; Workman P; Waterfield M. Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110alpha inhibitors. Bioorg Med Chem, 2006

Smith NF; Hayes A; James K; Nutley BP; McDonald E; Henley A; Dymock B; Drysdale MJ; Raynaud FI; Workman P. Preclinical pharmacokinetics and metabolism of a novel diaryl pyrazole resorcinol series of heat shock protein 90 inhibitors. Mol Cancer Ther 6: 1628-1637, 2006

Kaye SB; Workman P; Jackman AL. Potentiation of paclitaxel activity by the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin in human ovarian carcinoma cell lines with high levels of activated AKT. Mol Cancer Ther 5: 1197-1208, 2006

Workman P; Aboagye EO; Chung YL; Griffiths JR; Hart R; Leach MO; Maxwell RJ; McSheehy PM; Price PM; Zweit J; Cancer Research UK Pharmacodynamic / Pharmacokinetic Technologies Advisory Committee. Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. J Natl Cancer Inst 98: 580-598, 2006

Sanderson S; Valenti M; Gowan S; Patterson L; Ahmad Z; Workman P; Eccles SA. Benzoquinone ansamycin heat shock protein 90 inhibitors modulate multiple functions required for tumor angiogenesis. Mol Cancer Ther 5: 522-532, 2006

Newbatt Y; Burns S; Hayward R; Whittaker S; Kirk R; Marshall C; Springer C; McDonald E; Cancer Genome Project; Marais R; Workman P; Aherne W. Identification of inhibitors of the kinase activity of oncogenic V600E BRAF in an enzyme cascade high-throughput screen. J Biomol Screen 11: 145-154, 2006

da Rocha Dias S; Friedlos F; Light Y; Springer C; Workman P. Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. Cancer Res 65: 10686-10691, 2005

Collins I; Caldwell J; Fonseca T; Donald A; Bavetsias V; Hunter LJ; Garrett MD; Rowlands MG; Aherne GW; Davies TG; Berdini V; Woodhead SJ; Davis D; Seavers LC; Wyatt PG; Workman P, McDonald E. Structure-based design of isoquinoline-5-sulfonamide inhibitors of protein kinase B. Bioorg Med Chem 14: 1255-1273, 2006

Stimson L; Rowlands MG; Newbatt YM; Smith NF; Raynaud FI; Rogers P; Bavetsias V; Gorsuch S; Jarman M; Bannister A; Kouzarides T; McDonald E; Workman P; Aherne GW. Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity. Mol Cancer Ther 4: 1521-1532, 2005

Banerji U; Walton M; Raynaud F; Grimshaw R; Kelland L; Valenti M; Judson I; Workman P; Pharmacokinetic-pharmacodynamic relationships for the heat shock protein 90 molecular chaperone inhibitor 17-allylamino,17-demethoxygeldanamycin in human ovarian cancer xenograft models. Clin Cancer Res 11: 7023-7032, 2005

Raynaud F; Whittaker SR; Fischer PM; McClue S; Walton MI; Barrie SE; Garrett MD; Rogers P; Clarke SJ; Kelland LR; Valenti M; Brunton L; Eccles S; Lane DP; Workman P. In vitro and in vivo pharmacokinetic-pharmacodynamic relationships for the trisubstituted aminopurine cyclin-dependent kinase inhibitors olomoucine, bohemine and CYC202. Clin Cancer Res 11: 4875-4887, 2005

Dymock BW; Barril X; Brough PA; Cansfield JE; Massey A; McDonald E; Hubbard RE; Surgenor A; Roughley SD; Webb P; Workman P; Wright L; Drysdale MJ. Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design. J Med Chem 48: 4212-4215, 2005

Banerji U; O’Donnell A; Scurr M; Pacey S; Stapleton S; Asad Y; Simmons L; Maloney A; Raynaud F; Campbell M; Walton M; Lakhani S; Kaye S; Workman P; Judson I. Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino,17-demethoxygeldanamycin in patients with advanced malignancies. J Clin Oncol 23: 4152-4161, 2005

Cheung KM; Matthews TP; James K; Rowlands MG; Boxall KJ; Sharp SY; Maloney A; Roe SM; Prodromou C; Pearl LH; Aherne GW; McDonald E; Workman P. The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrzole class of Hsp90 inhibitors. Bioorg Med Chem Lett 15: 3338-3343, 2005

Chau NM; Rogers P; Aherne W; Carroll V; Collins I; McDonald E; Workman P; Ashcroft A. Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1alpha induction in response to hypoxic stress and growth factors. Cancer Res 65: 4918-4928, 2005

Clarke PA; te Poele R; Workman P. Gene expression microarray technologies in the development of new therapeutic agents. Eur J Cancer 40: 2560-2591, 2004

Wright L; Barril X; Dymock B; Sheridan L; Surgenor A; Beswick M; Drysdale M; Collier A; Massey A; Davies N; Fink A; Fromont C; Aherne W; Boxall K; Sharp S; Workman P; Hubbard RE. Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms. Chem Biol 11: 775-785, 2004

Kristeleit R; Stimson L; Workman P; Aherne W. Histone modification enzymes: novel targets for cancer drugs. Expert Opin Emerg Drugs 9: 135-154, 2004

Rowlands MG; Newbatt YM, Prodromou C; Pearl LH; Workman P; Aherne W. High-throughput screening assay for inhibitors of heat-shock protein 90 ATPase activity. Anal Biochem 327: 176-183, 2004

Workman P. Inhibiting the phosphoinositide 3-kinase pathway for cancer treatment. Biochem Soc Trans 32: 393-396, 2004

Raynaud FI; Fischer PM; Nutley BP; Goddard PM; Lane DP; Workman P. Cassette dosing pharmacokinetics of a library of 2,6,9-trisubstituted purine cyclin-dependent kinase 2 inhibitors prepared by parallel synthesis. Mol Cancer Ther 3: 353-362, 2004

Workman P. Combinatorial attack on multistep onocogenesis by inhibiting the Hsp90 molecular chaperone. Cancer Lett 206: 149-157, 2004

Workman P. Strategies for treating cancers caused by multiple genome abnormalities: from concepts to cures? Curr Opin Investig Drugs 4: 1410-1415, 2003

Whittaker SR; Walton MI; Garrett MD; Workman P. The cyclin-dependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of cyclin D1, and activates the mitogen-activated protein kinase pathway. Cancer Res 64: 262-272, 2004