Abstract 2782: Bcl-2 selective antagonists show antitumor activity without dose limiting platelet toxicity
Authors: Geneste Olivier , Murray James , Diguarher Thierry Le , Starck Jérome , Casara Patrick , Nanteuil Guillaume De , Davidson James , Nunns Claire , Graham Chris , Matassova Natalia , Chen Ijen , Whitehead Neil , Dokurno Pawel , Bruno Alain , Pierré Alain , Hickman John. A. , Wood Mike , Cruzalegui Francisco , Depil Stéphane 
Published: August 2012

Proteins of the Bcl-2 family are central regulators of programmed cell death. Pro-survival Bcl-2 proteins, such as Bcl-2, Bcl-xL and Mcl-1 are often over-expressed in human tumours and participate in tumour initiation, progression and chemo-resistance. Therefore drugs targeting these pro-survival Bcl-2 proteins represent a promising therapeutic approach for cancer treatment. The most advanced drug targeting this protein family is ABT-263, a potent Bcl-2 and Bcl-xL inhibitor showing anti-tumour efficacy in preclinical models of leukaemia and small cell lung carcinoma. Survival of circulating platelets has been shown to be highly Bcl-xL dependent; consequently the dose-limiting toxicity of ABT-263 is an on-target peripheral thrombocytopenia. We have used a range of biophysical methods to guide the structure-based generation of a significant number of small molecules,* which bind with high affinity (MW &lt; 780; KD &lt; 1 nM) to the BH3 binding groove of Bcl-2, and with high selectivity versus other members of the Bcl-2 family (selectivity &gt; 100 fold). In cellular assays, our lead compounds efficiently displace Bax from Bcl-2 with near complete inhibition of Bcl-2 / Bax co-immunoprecipitation at 100 nM. These compounds are strong inducers of cell death in Bcl-2 dependent cellular models such as the acute myeloblastic leukaemia (AML) cell line RS4;11, affording sub-10 nM IC50's for the most potent compounds. In vivo, in agreement with their mechanism of action, these Bcl-2 selective inhibitors, given either intravenously or orally, elicit a rapid (30 min iv, and 2 hours po) and strong apoptotic response in mouse xenografts of the RS4:11 cell line. When the most potent compounds are given orally to RS4;11 xenograft-bearing mice, apoptosis in tumor cells is induced more than 15 fold (at 25 mg/kg) and more than 20 fold (at 50 mg/kg) compared to untreated mice. Importantly, in agreement with the selectivity of the compounds for Bcl-2 versus Bcl-xL, no platelet loss was observed in mice treated with our compounds, in sharp contrast to ABT-263. Finally, we observe very robust anti-tumor activity when a lead compound is given orally at 50 mg/kg and 100 mg/kg (with complete regression at 100 mg/kg) in an RS4;11 mouse xenograft model. This anti-tumor activity was similar whether the compound was dosed daily or twice a week over two weeks. Altogether our data demonstrate that highly Bcl-2 selective antagonists show anti-tumor activity and no platelet toxicity, in contrast to Bcl-2 / Bcl-xL dual inhibitors. Such compounds represent promising drug candidates for the treatment of Bcl-2 dependent malignancies such as chronic lymphocytic leukaemia (CLL) and other leukaemias and lymphomas. * Chemical structures of compounds will not be disclosed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2782. doi:1538-7445.AM2012-2782