BRIDGEBIO PHARMA, INC. BBO-8520, a first-in-class, direct inhibitor of KRASG12C (ON), locks GTP-bound KRASG12C in the state 1 conformation resulting in rapid and complete blockade of effector binding
Pedro J. Beltran, Ph.D.
CSO, BridgeBio Oncology Therapeutics
BridgeBio Pharma, San Francisco, CA
Disclosure Information
Pedro J. Beltran, Ph.D.
I have the following relevant financial relationships to disclose: Employee of: BridgeBio Pharma Inc.
Stockholder in: BridgeBio Pharma Inc
BBO-8520: a first-in-class, direct inhibitor of KRASG12C (ON)
N O N
FN
N
F
F
S
CF3 CN NH2
• | Binds to the switch II pocket (Shokat) |
• | Forms covalent bond with C12 |
N O
• Locks GTP-bound KRASG12C (ON) in state 1 - |
unable to bind effectors |
NCI-H358
Assay
PPI Effector binding
Kinact/KI
pERK*
3D viability*
ED50/90
>50% CR
BBO-8520
33 nM
43,000 M-1S-1
- nM
- nM
0.6 / 1.6 mg/kg 10 mg/kg
• Potent KRASG12C activity with 200x selectivity | |
over WT KRAS | |
• | Tumor regressions @ 3 mg/kg QD |
• | Phase 1 ONKORAS-101 (NCT06343402) trial |
is now open |
*In vitro IC50 adjusted for free fraction in 10% FBS
Can KRAS inhibitors achieve levels of efficacy observed with other oncogene inhibitors in NSCLC?
Progression Free Survival
Best-in-class inhibitors in NSCLC
1sotorasib/
2adagrasib
3divarasib
(ON) state inhibitors
0
1st Gen KRASG12C OFF only
2nd Gen KRASG12C OFF only
?
10 20 30
Months
- Exquisite potency against the target
- Optimal target coverage
- Address main mechanisms of resistance/adaptation
- ORR >60%, PFS >15 month
1Skoulidis et. al NEJM 2021 3Sacher et. al NEJM 2023 2Janne et. al NEJM 2022
Inhibition of KRASG12C (ON) is necessary for optimal target coverage and prevention of adaptive mechanisms of resistance
Only GTP-bound KRASG12C | Increased GTP state is a | BBO-8520 inhibits both the |
activates effectors | MOA of adaptation to OFF | ON and OFF states of |
inhibitors | KRASG12C |
sotorasib adagrasib divarasib
BBO-8520
Yaeger et al Cancer Discovery 2023
Xue, et. al. Nature | Vol 577 | 16 January 2020
BBO-8520 modifies GTP-bound KRASG12C and inhibits effector binding
Unique ability to fully modify KRASG12C when GTP-bound
Potent inhibition of effector binding
MALDI-TOF | BBO-8520 | sotorasib | adagrasib | divarasib | |
% Modified | |||||
GTP | 15' | 100 | 0 | 0 | 0 |
60' | 100 | 0 | 0 | 0 | |
Excitation: 320 nm
FRET
Streptavidin-TbAvi-KRASGpp (Donor)
RBD-FLAG
Mab-FLAG
XL665
(Acceptor)
Emission: 665 nm
GDP | 15' | 91 | 80 | 73 | 77 | |
60' | 100 | 82 | 84 | 84 | ||
Effector | ||||||
Binding IC50 | 33 | >100,000 | 20,000 | 4,200 | ||
(nM) | ||||||
GTP Kinact/KI | 20,000 | 0 | 0 | 0 | ||
(M-1S-1) | ||||||
GDP Kinact/KI | 2,743,000 | 11,000 | 180,000 | 1,100,000 |
%Activity
120 | |||
100 | |||
80 | |||
60 | |||
40 | |||
20 | |||
0 | |||
0.0001 0.001 | 0.01 | 0.1 | 1 |
sotorasib adagrasib divarasib
BBO-8520
10 100
(M-1S-1) |
Cmpd (log ∝M)
BBO-8520: Binding mode is clinically validated
BBO-8520 binds in the pocket between Switch II and alpha Helix 3
KRAS-G12C(GDP):BBO-8520 | KRAS-G12C(GppNHp):BBO-8520 | Dimethylpiperazine rotates ~180o |
in the presence of trinucleotide |
D92 | ||
H95 | ||
Q99 | ||
C12 | Y96 | |
K16 | ||
Y64 | ||
GDP | E62 | R102 |
D69
Q61 R68
E63
D92 | ||
H95 | ||
Q99 | ||
C12 | Y96 | |
K16 | ||
Y64 | ||
E62 | R102 |
GTP
D69 | |
Q61 | R68 |
E63 | |
Y96
K16 | E62 | |
C12 | ||
Q61 | ||
A59 | G60 | |
GDPGTP
BBO-8520: Mechanism of action & selectivity
31P NMR spectrum: State 1 trapping | Cellular Selectivity | ||
Global Cysteine Proteomics (20 nM) | |||
-log10(P-value)
- KRAS 12 (P=0.00072)
Log2(Ratio) | ||||||
State 1 | State 2 | |||||
BBO-8520: Consistent, sub-nanomolar effect in multiple KRASG12C models
Signaling (HTRF®) | Viability (CellTiterGlo®) | Clonogenic (Incucyte ®) |
BBO-8520 pERK (Free IC50,nM)
1000
100
10
1
0.1
0.01
G12C G12D G12V G12S | WT | V600E | G12C G12C G12C |
KRAS KRAS KRAS KRAS | KRAS | ||
KRAS KRAS KRAS | |||
BRAF | |||
Sotorasib | Divarasib | ||
Adagrasib |
BBO-8520 3D Viability (Free IC50,nM)
1000
100
10
1
0.1
0.01
G12C G12D G12V G12S | WT | V600E | G12C G12C | G12C |
KRAS KRAS KRAS KRAS | KRAS | |||
KRAS KRAS KRAS | ||||
BRAF | ||||
Sotorasib | Divarasib | |||
Adagrasib |
100 | ||||
Confluence | 80 | |||
40 | ||||
60 | ||||
% | 20 | |||
0 | ||||
0 | 10 | 20 | 30 |
Day
Vehicle
22.5 nM sotorasib 10 nM adagrasib
75 nM sotorasib | 30 nM adagrasib | |
40
- nM BBO-8520
- nM BBO-8520
- nM BBO-8520
Cell Line | H358 | MIA PaCa-2 | Calu-1 | H2030 | LU99 | SW837 | SW1463 | UM-U-C3 |
Viability IC50 | 0.032 | 0.037 | 0.015 | 0.015 | 0.015 | 0.041 | 0.055 | 0.023 |
(nM) | ||||||||
In vitro IC50 adjusted for free fraction in 10% FBS
BBO-8520: Demonstration of differentiated cellular KRASG12C (ON) activity
RAS:RAF1 ELISA Assay | G12C/A59G Transitional state mutant |
120 | |||||||
RAS-RAF | 100 | ||||||
80 | |||||||
60 | |||||||
40 | |||||||
% | |||||||
20 | |||||||
0 | 10 | 20 | 30 | 40 | 50 | 60 | |
0 | |||||||
Minutes |
sotorasib divarasib
adagrasib BBO-8520
In vitro IC50 adjusted for free fraction in 10% FBS
KRAS pERK Total ERK Vinculin
Growth factor swift assay (H358 +/- EGF)
120 | 120 | ||||||||||||||
sotorasib | |||||||||||||||
100 | 100 | ||||||||||||||
%pERK | 80 | pERK% | 80 | adagrasib | |||||||||||
40 | 40 | BBO-8520 | |||||||||||||
60 | 60 | ||||||||||||||
20 | 20 | +EGF | |||||||||||||
0 | 0 | ||||||||||||||
0.01 | 0.1 | 1 | 10 | 100 | 1000 | 10000 | 0.01 | 0.1 | 1 | 10 | 100 | 1000 | 10000 | ||
Comd [nM] | Cmpd (nM) |
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BridgeBio Pharma Inc. published this content on 23 April 2024 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 23 April 2024 20:17:53 UTC.
