BAY 80-6946 is a Highly Selective Intravenous PI3K Inhibitorwith Potent p110α and p110δ Activities in Tumor Cell Linesand Xenograft Models

1. BAY 80-6946 is a Highly Selective
Intravenous PI3K Inhibitor
with Potent p110α and p110δ
Activities in Tumor Cell Lines
and Xenograft Models
Presented by- Bisshojit Biswas

2. Bibliography
• Ningshu Liu, Bruce R. Rowley†, Cathy O. Bull, Claudia
Schneider, Andrea Haegebarth, Christoph A. Schatz,Paul R.
Fracasso, Dean P. Wilkie, Martin Hentemann, Scott M.
Wilhelm, William J. Scott, Dominik Mumberg,and Karl
Ziegelbauer.
• Molecular Cancer Therapeutics volume 12 (11), pages
2319-2330 (November, 2013)

3. BAY 80-6946
• Chemical name- [2-amino-N-[7-methoxy-8-(3-
morpholinopropoxy)-2,3-dihydroimidazo[1,2-
c]quinazolin]
Fig: BAY 80-6946 or
copanlisib

4. Main Goal of this study
• To develop another PI3K inhibitor with different
pharmacokinetic & Pharmacologic profile, which will help
in the exploration of different indication, combination &
dosing regimen.
• To establish BAY 80-6946 as a highly selective
Phosphoionsitide 3- Kinase (PI3K) inhibitor in preclinical
studies.
• To observe it’s activity against PI3Kα & PI3Kδ.
• It has superior antitumor activity in PIK3CA mutant, breast
cancer cell line.

5. Main in vivo findings
• Intravenous administration of BAY 80-6946 show higher
exposure & prolonged inhibition of pAKT levels in tumor
compare to plasma.
• It is efficacious in tumors with activated PI3k, in either
continuous or intermittent dosing.
• It induces 100% tumor regression when dosed as a single
agent at every second day in HER 2 amplified & PIK3CA
mutated KPL4 breast tumor.
• In combination with paclitaxel, weekly dosing of BAY 80-
6946 is sufficient to reach sustained response in all animals
NSCLC xenograft model. Although a short plasma
elimination half life in mice .

6. Xenograft model
• Here athymic nude rats & nude mice
were used for xenograft models of human
tumors.
• Animals were housed according to
institutional guide lines with excess to
food & water ad libitum.
• Studies with patient derived tumor were
conducted in Epo GmbH.
• Tumor xenograft were generated by
harvesting cells from mid – log phase
cultures & then injected subcutaneously
in the right flank of each rat & mice.
• BAY 80-6946 was dissolved in PEG 400/
acidified water/ 5% mannitol vehicle.

7. Continued...
• Treatment was initiated after the
establishment of tumor.
• Drug was given intravenously at Q2D,
Q3D or weekly at indicated doses.
• Tumor dimensions & body weight were
recorded twice weekly starting from the
first day of treatment. From this tumor
volume was calculated.
• Anti tumor efficacy was determined by
% TGI.
• In addition , treatment response rate
were evaluated by means of clinically
used RECIST criteria.

8. BAY 80-6946 is highly efficacious in rat and mouse
tumor xenograft models following intravenous
administration
• The MTD in rat were 6 mg/kg
• The MTD in mice were 14 mg/kg with every second
day dosing.

9. Figure 5. Activity of BAY 80-6946 in xenograft models using an every
second day (Q2D) schedule.
A, KPL4 breast cancer xenografts in nude rats (10 rats/group).
Continued..

10. Figure 5. Activity of BAY 80-6946 in xenograft models using an
every second day (Q2D) schedule.
B, HCT116 colon cancer xenografts in nude rats (10 rats/group).
Continued..

11. Figure 5. Activity of BAY 80-6946 in xenograft models using an every second day
(Q2D) schedule.
C, Lu7860 erlotinib-resistant, patient-derived NSCLC xenografts in nude mice
(5 mice/group).
Continued..

12. Figure 5. Activity of BAY 80-6946 in xenograft models using an
every second day (Q2D) schedule.
D, MAXF1398 patient-derived luminal breast cancer xenografts
in nude mice (6 mice/group).
Continued..

13. Article link
• https://www.researchgate.net/publicati
on/258148474_BAY_80-
6946_Is_a_Highly_Selective_Intravenous
_PI3K_Inhibitor_with_Potent_p110_and_
p110_Activities_in_Tumor_Cell_Lines_an
d_Xenograft_Models

14. THANK YOU