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Title: The Design and Synthesis of Phospholipase C Gamma Inhibitors.
Author: Day , James Edward Harvey
ISNI:       0000 0001 3419 0293
Awarding Body: Institute of Cancer Research (University Of London)
Current Institution: Institute of Cancer Research (University Of London)
Date of Award: 2008
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Phospholipase C (PLC) catalyses the hydrolysis of phosphatidylinositoI4,5-biphosphate to two important secondary messengers which mediate downstream cell motility and cell proliferation. PLCy is of particular interest because of its involvement with growth factor mediated cell motility, which is a key process to both angiogenesis and tumour invasion. Experimental results provide compelling evidence that PLCy may be rate limiting in tumour invasion and angiogenesis. There is a need for efficacious and 'drug like' inhibitors ofPLCy. Two compounds CCT006000 and CCT007740 were identified from a high throughput biochemical screen against PLCy2. An initial investigation into their structure activity relationships led to the conclusion that CCT007740 (PLCy2 50% inhibitory concentration (ICso) 50 JlM) was a promising candidate for further development. A series of structural modifications to CCT007740 and subsequent optimisation produced CCTl29010 (PLCy2 ICso 1.7 JlM). Although CCTl29010 had improved potency, the compound was degraded rapidly by mouse liver microsomes (MLM) and lacked cellular activity. Further exploration and manipulation of CCTl29010 led to the discovery of CCTl30234 (PLCy2 ICso 480 nM). The compound displays the cellular signature expected that of a PLCy inhibitor; inhibiting growth factor induced HUVEC migration and calcium release. CCTl32034 is stable to MLM and has good pharmacokinetic properties. CCTl30234 significantly inhibited metastasis in a highly invasive prostate carcinoma model, further validating PLCy as an important cancer drug target.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available