CRT0066101, a small molecule inhibitor of protein kinase D, demonstrates in vitro and in vivo anticancer efficacy


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Stephen Jamieson, Azadeh Bagherzadeh, Mark Charles, Neil Jones, Florence Chan, Rachel Sutherland, Gregoire Pave, Julia Gilliatt, Kevin Stewart, Tim Hammonds, Caroline Foxton, Tony Raynham, Lloyd Kelland, Christopher Ireson

Cancer Research Technology Discovery Laboratories, University College London, London, UK

Abstract

Protein Kinase D (PKD) has been shown to play an important role in promoting tumour proliferation, angiogenesis and cell survival. As such, PKD represents a promising novel target for therapeutic intervention in cancer.

We have developed 2 series of structurally-distinct small molecule inhibitors of PKD that phenocopy the antiproliferative and apoptotic effects of siRNA-mediated knockdown of PKD. Chemical optimisation of series 1 resulted in the selection of a lead PKD inhibitor, CRT0066101, with sub nM biochemical IC50 potency, favourable ADME properties and a clean selectivity profile against other kinases. CRT0066101 had sub μM potency against phorbol ester-stimulated PKD1 serine 916 autophosphorylation, a biomarker of PKD activity, in a variety of human cancer cell lines, including panc1, A549 and PC3M. In addition, treatment with CRT0066101 resulted in an inhibition of proliferation and a marked induction of apoptosis in these cell lines. Mouse pharmacokinetic studies revealed that CRT0066101 is orally bioavailable and that drug levels in excess of those required to inhibit PKD and induce anti-proliferative and apoptotic effects in vitro are achievable following administration of a single dose of 10 mg/kg CRT0066101 by oral gavage. Furthermore, chronic dosing in mice of CRT0066101 by oral gavage (80 mg/kg for 5 days a week) caused a reduction in tumour growth rate in a panc1 xenograft model and increased tumour doubling time, a surrogate marker of survival.

These data indicate that inhibiting PKD is an effective anticancer strategy and support the progression of PKD inhibitors, such as CRT0066101, into clinical studies.

Protein Kinase D (PKD) has been shown to play an important role in promoting tumour proliferation, angiogenesis and cell survival. As such, PKD represents a promising novel target for therapeutic intervention in cancer.

We have developed 2 series of structurally-distinct small molecule inhibitors of PKD that phenocopy the antiproliferative and apoptotic effects of siRNA-mediated knockdown of PKD. Chemical optimisation of series 1 resulted in the selection of a lead PKD inhibitor, CRT0066101, with sub nM biochemical IC50 potency, favourable ADME properties and a clean selectivity profile against other kinases. CRT0066101 had sub μM potency against phorbol ester-stimulated PKD1 serine 916 autophosphorylation, a biomarker of PKD activity, in a variety of human cancer cell lines, including panc1, A549 and PC3M. In addition, treatment with CRT0066101 resulted in an inhibition of proliferation and a marked induction of apoptosis in these cell lines. Mouse pharmacokinetic studies revealed that CRT0066101 is orally bioavailable and that drug levels in excess of those required to inhibit PKD and induce anti-proliferative and apoptotic effects in vitro are achievable following administration of a single dose of 10 mg/kg CRT0066101 by oral gavage. Furthermore, chronic dosing in mice of CRT0066101 by oral gavage (80 mg/kg for 5 days a week) caused a reduction in tumour growth rate in a panc1 xenograft model and increased tumour doubling time, a surrogate marker of survival.

These data indicate that inhibiting PKD is an effective anticancer strategy and support the progression of PKD inhibitors, such as CRT0066101, into clinical studies.

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