The Bcl3 Story : Collabora2ve Drug Discovery In Ac2on
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1 The Bcl3 Story : Collabora2ve Drug Discovery In Ac2on Dr Andrew Westwell Drug Development & Model Systems Package Lead Dr Luke Piggo> Research Associate, WCRC Rachel Savery Trials Project Manager (Early Phase) Dr Tim Robinson CRUK Clinical Fellow
2 Bcl3 Oct 2007 target in BC Small screening Jul 2013 Provisional GB patent filing JS6 identfied as lead Sep 2013 BioVitas license IP April 2014 Tiziana Life sciences launched Sep 2015 Clinical Trial lead cpd identfied July 14- Phase 1 trial design Pt recruitment Medicines agency/ manufacture/ efficacy Phase 2/Phase 3 design
3 Compound number 10, Costs (M$)
4 The Role of Bcl Bcl3 is a transcripton factor that reads DNA and belongs to the NFkB signaling pathway Bcl3 needs to form a complex with other factors such as p50 to perform it s functon These complexes will then bind to DNA to regulate gene expression
5 Bcl3 Target Valida2on - Bcl3 does not drive primary tumour growth - Bcl3 promotes tumor metastasis spontaneous sirna sirna control Bcl3 xenografs - Bcl3 Drives metasta2c spread - Bcl3 Deficient mice are viable
6 Bcl3 Oct 2007 target in BC
7 Building the Bcl3 Model Ankyrin repeat
8 Building the Bcl3 Model IκBα Bcl3 The Bcl3 structure was partally available The Ankyrin repeat domain is sufficient for interacton with binding proteins Bcl3 The related structure of IκBα in complex with p50 is also available p50 p50
9 Building the Bcl3 Model Bcl3 p50 Bcl3 p50
10 Building the Bcl3 Model Bcl3 p50 Bcl3 p50
11 Virtual Screening Pocket Iden2fica2on
12 Virtual Screening Pocket Iden2fica2on
13 Virtual Screening Pocket Iden2fica2on
14 Virtual Screening Pocket Iden2fica2on
15 Bcl3 Small screening Oct 2007 target in BC
16 Virtual Screening Docking and Scoring 1. Design of a pharmacophore based on the interactons between the two protein 2. Filtering of the SPECS library (~300,000 cpds) through the pharmacophore 3. Hit compounds (~16,000) docked using three different sofwares 4. Docking results ranked via a custom consensus scoring functons 5. Top 121 compounds were examined and further analysed via another set of scoring functons.
17 Virtual Screening - Summary The top 10 compounds were purchased and tested in 4 in vitro assays
18 Compound Evalua2on 1. Cancer cell cytotoxicity how well does each compound kill cancer cells? 2. Binding Assay Does the compound specifically inhibit the binding of Bcl3? 3. FuncTonal Assay How well does the compound interfere with the acton of Bcl3? 4. MigraTon Assay Does the compound prevent cell migraton? 5. In vivo analysis Does the compound prevent metastasis in animals?
19 Bcl3 Oct 2007 target in BC Small screening JS6 identfied as lead
20 Compounds Evalua2on In vivo evalua2on - Metasta2c breast cancer Control Tumour burden over Tme JS6 3.5mg/Kg Con JS6
21 Bcl3 Oct 2007 target in BC Small screening Jul 2013 Provisional GB patent filing JS6 identfied as lead
22 Bcl3 Oct 2007 target in BC Small screening Sep 2013 BioVitas license IP JS6 identfied as lead Jul 2013 Provisional GB patent filing
23 Bcl3 Oct 2007 target in BC Small screening Jul 2013 Provisional GB patent filing JS6 identfied as lead Sept 2013 BioVitas license IP April 2014 Tiziana Life sciences launched spin- off
24 Compound Evalua2on MetastaTc Breast Cancer Compound injecton P h o to n c o u n ts x P e rc e n t s u rv iv a l T h o r a c ic tu m o u r b u r d e n o v e r tim e D is e a s e fr e e s u r v iv a l V e h ic le n = 6 V e h ic le C B 1 n = 1 0 C B M e a n m e ta s ta tic b u r d e n a n d T F S P h o to n c o u n ts x a t d a y /6 4 /1 0 T F S V e h ic le C B D aay ys s n = 6 n = 1 0
25 Compound Evalua2on M e ta s ta tic p ro g re s s io n a fte r in tra v e n io u s in je c tio n o f M D A -M B L U C c e lls P h o to n c o u n ts x V e h ic le n = C B m g /k g n = 5 C B m g /k g n = D a y s M e a n m e ta s ta tic b u r d e n a n d T F S a t d a y 2 8 P h o to n c o u n ts x M e a n m e ta s ta tic b u r d e n a n d T F S a t d a y /5 1 /5 2 /5 T F S V e h ic le C B m g /k g * C B m g /k g P h o to n c o u n ts x /5 0 /5 0 /5 T F S * MetastaTc Breast Cancer Oral AdministraTon of compound V e h ic le C B m g /k g C B m g /k g
26 Compound Evalua2on Colorectal Cancer T u m o r v o lu m e [m m 3 ] T u m o u r s iz e o v e r tim e n o r m a liz e d to c o n tr o l V e h ic le C B 1 n = 8 n = 1 0 T u m o r v o lu m e [m m 3 ] T u m o u r s iz e a t d a y 1 5 n o r m a liz e d to c o n tr o l * * * * T u m o r v o lu m e [m m 3 ] S in g le tu m o u r s iz e a t d a y 1 5 n o r m a liz e d to c o n tr o l D a y s 0 V e h ic le C B 1 0 V e h ic le V e h ic le V e h ic le V e h ic le V e h ic le V e h ic le V e h ic le V e h ic le C B 1 C B 1 C B 1 C B 1 C B 1 C B 1 C B 1 C B 1 C B 1 C B 1
27 Bcl3 Oct 2007 target in BC Small screening Jul 2013 Provisional GB patent filing JS6 identfied as lead Sep 2013 BioVitas license IP April 2014 Tiziana Life sciences launched Sep 2015 Clinical Trial lead cpd identfied
28 SupporTng TransiTon from Bench to Bedside
29 Bcl3 Oct 2007 target in BC Small screening Jul 2013 Provisional GB patent filing JS6 identfied as lead Sep 2013 BioVitas license IP April 2014 Tiziana Life sciences launched Sep 2015 Clinical Trial lead cpd identfied July 14- Phase 1 trial design Pt recruitment
30 Clinical Trial Design Designing Phase 1
31 Bcl3i Phase 1 Trial Design 3+3 Design Cardiff led, mult- centre Phase 1 study Assess: PK/PD, safety and biomarkers Dose 6 Dose 5 Dose 4 Dose 3 Maximum tolerated or biologically effectve dose Assessment of response/actvity (PFS/OS) Dose 1 Dose 2 Dose Escala2on - All tumour types PredicTve biomarker n = up to 36 analysis n = 14 Dose Expansion Metasta2c breast cancer
32 Bcl3 Oct 2007 target in BC Small screening Jul 2013 Provisional GB patent filing JS6 identfied as lead Sep 2013 BioVitas license IP April 2014 Tiziana Life sciences launched Sep 2015 Clinical Trial lead cpd identfied July 14- Phase 1 trial design Pt recruitment Phase 2/Phase 3 design
33 Bcl3i Trial Design Phase 2 Evidence of safety and actvity/biological actvity MetastaTc triple negatve breast cancer, post- chemotherapy- trying to delay relapse Assess PFS/OS Phase 3 Use afer standard adjuvant/neo- adjuvant treatment- trying to delay relapse Assessment of PFS/OS
34 Bcl3 Oct 2007 target in BC Small screening Jul 2013 Provisional GB patent filing JS6 identfied as lead Sep 2013 BioVitas license IP April 2014 Tiziana Life sciences launched Sep 2015 Clinical Trial lead cpd identfied July 14- Phase 1 trial design Pt recruitment Medicines agency/ manufacture/ efficacy Phase 2/Phase 3 design
35 Poten2al Bcl3i Licencing and Approval EMA/FDA licensing Ac2ve compound manufacture (GMP) GLP toxicology (chromic dosing) Formula2on for oral delivery.
36 ACKNOWLEDGEMENTS Cardiff University Richard Clarkson Andrea Brancale Alison Wakefield Jitka Soukupová Cinzia Bordoni Daniel Turnham Will Yang Aleksandra Gruca Alicia Derrac Soria Tiziana Life Sciences Gabriele Cerrone Phil Boyd Chris McGuigan
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