Cat. No.: HY-161233

BTX-6654

BTX-6654 is a SOS1 PROTAC degrader. BTX-6654 induces ubiquitination and degradation of SOS1 via the proteasomal pathway by bridging SOS1 with the E3 ligase CRBN to form a ternary complex, thereby blocking KRAS activation and downregulating the MAPK signaling pathway (pERK/pS6), and ultimately inhibiting tumor growth. BTX-6654 can be used in research on various cancers driven by KRAS mutations.
(Pink: SOS1 ligand (HY-175896); Blue: Cereblon ligand (HY-138881); Black: linker).

For research use only. We do not sell to patients.

Formula: C₅₀H₅₇F₄N₉O₅
Molecular Weight:940.04

Storage:

Please store the product under the recommended conditions in the Certificate of Analysis.

Data Sheet (276 KB)

BTX-6654 Chemical Structure

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Use of MCE Products

Strong Fluorescence Signal / Multi-Disciplinary Applications / High Fluorescence Specificity

Biological Activity
- Description
- Cellular Effect
- In Vitro
- In Vivo
Chemical Information
Purity & Documentation
References
Calculators
Help & FAQs
Classifications
Bioz

Biological Activity

Description

BTX-6654 is a SOS1 PROTAC degrader. BTX-6654 induces ubiquitination and degradation of SOS1 via the proteasomal pathway by bridging SOS1 with the E3 ligase CRBN to form a ternary complex, thereby blocking KRAS activation and downregulating the MAPK signaling pathway (pERK/pS6), and ultimately inhibiting tumor growth. BTX-6654 can be used in research on various cancers driven by KRAS mutations^[1]. (Pink: SOS1 ligand (HY-175896); Blue: Cereblon ligand (HY-138881); Black: linker).

All PROTACs Isoforms :

All ERK Isoforms :

All p38 MAPK Isoforms :

Cellular Effect

Cell Line	Type	Value	Description	References
NCI-H2009	IC50	26.8 nM	Cell viability inhibitory activity against human KRAS G12A heterozygous lung NCI-H2009 cells. Cell viability inhibitory activity against human KRAS G12A heterozygous lung NCI-H2009 cells.	38224565
NCI-H1573	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12A heterozygous lung NCI-H1573 cells. Cell viability inhibitory activity against human KRAS G12A heterozygous lung NCI-H1573 cells.	38224565
SW837	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12C homozygous colon SW837 cells. Cell viability inhibitory activity against human KRAS G12C homozygous colon SW837 cells.	38224565
NCI-H1792	IC50	107.2 nM	Cell viability inhibitory activity against human KRAS G12C heterozygous lung NCI-H1792 cells. Cell viability inhibitory activity against human KRAS G12C heterozygous lung NCI-H1792 cells.	38224565
NCI-H23	IC50	34.2 nM	Cell viability inhibitory activity against human KRAS G12C heterozygous lung NCI-H23 cells. Cell viability inhibitory activity against human KRAS G12C heterozygous lung NCI-H23 cells.	38224565
NCI-H358	IC50	7.6 nM	Cell viability inhibitory activity against human KRAS G12C heterozygous lung NCI-H358 cells. Cell viability inhibitory activity against human KRAS G12C heterozygous lung NCI-H358 cells.	38224565
NCI-H2122	IC50	51.5 nM	Cell viability inhibitory activity against human KRAS G12C homozygous lung NCI-H2122 cells. Cell viability inhibitory activity against human KRAS G12C homozygous lung NCI-H2122 cells.	38224565
NCI-H2030	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12C homozygous lung NCI-H2030 cells. Cell viability inhibitory activity against human KRAS G12C homozygous lung NCI-H2030 cells.	38224565
SW1573	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12C homozygous lung SW1573 cells. Cell viability inhibitory activity against human KRAS G12C homozygous lung SW1573 cells.	38224565
MIA PaCa-2	IC50	1.2 nM	Cell viability inhibitory activity against human KRAS G12C homozygous pancreas MIA PaCa-2 cells. Cell viability inhibitory activity against human KRAS G12C homozygous pancreas MIA PaCa-2 cells.	38224565
GP2D cell	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12D heterozygous colon GP2D cells. Cell viability inhibitory activity against human KRAS G12D heterozygous colon GP2D cells.	38224565
LS-513	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12D heterozygous colon LS513 cells. Cell viability inhibitory activity against human KRAS G12D heterozygous colon LS513 cells.	38224565
A-427	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12D heterozygous colon A427 cells. Cell viability inhibitory activity against human KRAS G12D heterozygous colon A427 cells.	38224565
AGS	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12D heterozygous stomach AGS cells. Cell viability inhibitory activity against human KRAS G12D heterozygous stomach AGS cells.	38224565
SW-620	IC50	52.5 nM	Cell viability inhibitory activity against human KRAS G12V homozygous colon SW620 cells. Cell viability inhibitory activity against human KRAS G12V homozygous colon SW620 cells.	38224565
COLO-668	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12V homozygous lung COLO 668 cells. Cell viability inhibitory activity against human KRAS G12V homozygous lung COLO 668 cells.	38224565
LCLC-97TM1	IC50	21.8 nM	Cell viability inhibitory activity against human KRAS G12V homozygous lung LCLC97-TM1 cells. Cell viability inhibitory activity against human KRAS G12V homozygous lung LCLC97-TM1 cells.	38224565
NCI-H441	IC50	14.7 nM	Cell viability inhibitory activity against human KRAS G12V heterozygous lung NCI-H441 cells. Cell viability inhibitory activity against human KRAS G12V heterozygous lung NCI-H441 cells.	38224565
NCI-H727	IC50	135.3 nM	Cell viability inhibitory activity against human KRAS G12V heterozygous lung NCI-H727 cells. Cell viability inhibitory activity against human KRAS G12V heterozygous lung NCI-H727 cells.	38224565
NCI-H2444	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G12V homozygous lung NCI-H2444 cells. Cell viability inhibitory activity against human KRAS G12V homozygous lung NCI-H2444 cells.	38224565
A549	IC50	1.2 nM	Cell viability inhibitory activity against human KRAS G12S homozygous lung A549 cells. Cell viability inhibitory activity against human KRAS G12S homozygous lung A549 cells.	38224565
LS-123	IC50	18.8 nM	Cell viability inhibitory activity against human KRAS G12S heterozygous colon LS123 cells. Cell viability inhibitory activity against human KRAS G12S heterozygous colon LS123 cells.	38224565
NCI-H1734	IC50	68.5 nM	Cell viability inhibitory activity against human KRAS G13C heterozygous lung NCI-H1734 cells. Cell viability inhibitory activity against human KRAS G13C heterozygous lung NCI-H1734 cells.	38224565
TOV21G	IC50	47.0 nM	Cell viability inhibitory activity against human KRAS G13C heterozygous ovary TOV-21G cells. Cell viability inhibitory activity against human KRAS G13C heterozygous ovary TOV-21G cells.	38224565
DLD-1	IC50	111.3 nM	Cell viability inhibitory activity against human KRAS G13D heterozygous colon DLD-1 cells. Cell viability inhibitory activity against human KRAS G13D heterozygous colon DLD-1 cells.	38224565
LoVo	IC50	73.7 nM	Cell viability inhibitory activity against human KRAS G13D heterozygous colon LoVo cells. Cell viability inhibitory activity against human KRAS G13D heterozygous colon LoVo cells.	38224565
HCT-116	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G13D heterozygous colon HCT116 cells. Cell viability inhibitory activity against human KRAS G13D heterozygous colon HCT116 cells.	38224565
NCI-H1944	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS G13D heterozygous lung NCI-H1944 cells. Cell viability inhibitory activity against human KRAS G13D heterozygous lung NCI-H1944 cells.	38224565
SJSA-1	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS Q61H heterozygous bone SJSA-1 cells. Cell viability inhibitory activity against human KRAS Q61H heterozygous bone SJSA-1 cells.	38224565
NCI-H460	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS Q61H homozygous lung NCI-H460 cells. Cell viability inhibitory activity against human KRAS Q61H homozygous lung NCI-H460 cells.	38224565
MKN-1	IC50	26.2 nM	Cell viability inhibitory activity against human KRAS wild-type amplified stomach MKN-1 cells. Cell viability inhibitory activity against human KRAS wild-type amplified stomach MKN-1 cells.	38224565
RL95-2	IC50	8.5 nM	Cell viability inhibitory activity against human HRAS Q61H heterozygous uterus RL95-2 cells. Cell viability inhibitory activity against human HRAS Q61H heterozygous uterus RL95-2 cells.	38224565
NCI-H1299	IC50	>2500 nM	Cell viability inhibitory activity against human NRAS Q61K heterozygous lung NCI-H1299 cells. Cell viability inhibitory activity against human NRAS Q61K heterozygous lung NCI-H1299 cells.	38224565
EBC-1	IC50	17.8 nM	Cell viability inhibitory activity against human EGFR L858R mutant lung EBC-1 cells. Cell viability inhibitory activity against human EGFR L858R mutant lung EBC-1 cells.	38224565
NCI-H1975	IC50	2.4 nM	Cell viability inhibitory activity against human EGFR L858R/T790M mutant lung NCI-H1975 cells. Cell viability inhibitory activity against human EGFR L858R/T790M mutant lung NCI-H1975 cells.	38224565
HCC827	IC50	63.4 nM	Cell viability inhibitory activity against human EGFR ex19del mutant lung HCC-827 cells. Cell viability inhibitory activity against human EGFR ex19del mutant lung HCC-827 cells.	38224565
U-87MG ATCC	IC50	12.9 nM	Cell viability inhibitory activity against human NF1 F1423M heterozygous brain U87MG cells. Cell viability inhibitory activity against human NF1 F1423M heterozygous brain U87MG cells.	38224565
SK-N-FI	IC50	43.7 nM	Cell viability inhibitory activity against human NF1 partial deletion homozygous brain SK-N-FI cells. Cell viability inhibitory activity against human NF1 partial deletion homozygous brain SK-N-FI cells.	38224565
A2058	IC50	>2500 nM	Cell viability inhibitory activity against human BRAF V600E heterozygous skin A2058 cells. Cell viability inhibitory activity against human BRAF V600E heterozygous skin A2058 cells.	38224565
A-375	IC50	>2500 nM	Cell viability inhibitory activity against human BRAF V600E homozygous skin A375 cells. Cell viability inhibitory activity against human BRAF V600E homozygous skin A375 cells.	38224565
NCI-H520	IC50	>2500 nM	Cell viability inhibitory activity against human KRAS-null lung NCI-H520 cells. Cell viability inhibitory activity against human KRAS-null lung NCI-H520 cells.	38224565

In Vitro

Anti-cancer

BTX-6654 potently inhibits the viability of specific human cancer cell lines (including MIA PaCa-2, A549, NCI-H1975 and SNU-175) with IC₅₀ values as low as 1.2 nM, but shows no significant activity against many other cancer cell lines with specific KRAS, NRAS, BRAF, NF1 mutations or KRAS deletion status (IC₅₀ > 2500 nM)^[1].
BTX-6654 (0.1 nM-10 µM; 24 h) induces significant, target-dependent and specific SOS1 degradation in MIA PaCa-2 and LoVo cells^[1].
BTX-6654 (200 nM; eluted for 24 h after 24 h of treatment) sustains persistent degradation of SOS1 in MIA PaCa-2 and LoVo cells^[1].
BTX-6654 (50-200 nM; 1-6 h) exhibits time-dependent and selective SOS1 degradation activity in MIA PaCa-2 and LoVo cells^[1].
BTX-6654 (50-200 nM; 6 h) exhibits rescued SOS1 degradation when combined with CC-220 (HY-101291) (10 µM) in MIA PaCa-2 and LoVo cells, and shows blocked SOS1 degradation when combined with MG132 (HY-13259) (10 µM) or MLN4924 (HY-70062) (1 µM) in MIA PaCa-2 and LoVo cells^[1].
BTX-6654 (50-200 nM; 6 h) induces degradation of wild-type SOS1 in H358 transgenic cells expressing FLAG-SOS1 WT, but exhibits no degradation activity in cells expressing the H905V or N879A/H905V mutants^[1].
BTX-6654 (0.8-500 nM; 24 h) reduces the activity of downstream pERK, pS6 and pAKT signaling in MIA PaCa-2 cells, and inhibits pERK and pS6 phosphorylation in LoVo and A549 cells^[1].
BTX-6654 (100-500 nM; 6 h) combines with CC-220 (10 µM) results in the rescue of pERK and pS6 inhibition in LoVo cells.^[1].
BTX-6654 (0.01 pM-100 µM; 5-6 days in 3D culture or 3 days in 2D culture) significantly inhibits cell proliferation in EBC-1, NCI-H358, and MIA PaCa-2 cells, with IC₅₀ values of 17.8 nM, 1.12 nM, and 7.5 nM, respectively, while exhibiting extremely low cytotoxicity in normal HEK293 and NHLF cell lines^[1].
BTX-6654 (0.01 pM-10 µM; 5-6 days) does not reduce cell viability in MIA PaCa-2 (SOS1 KO) cells, indicating that its proliferation inhibitory activity is SOS1-dependent^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Western Blot Analysis^[1]

Cell Line:

MIA PaCa-2, LoVo
Concentration:

50, 200 nM
Incubation Time:

1, 2, 4, 6 h
Result:

Resulted in time-dependent, maximal degradation of SOS1 within 6 hours.

Western Blot Analysis^[1]

Cell Line:

MIA PaCa-2, LoVo
Concentration:

50, 200 nmol/L (+ CC-220, MG132 or MLN4924)
Incubation Time:

6 h
Result:

Induced degradation of SOS1 was completely blocked by the CRBN ligand or proteasome/NEDD8 inhibitors.

Western Blot Analysis^[1]

Cell Line:

MIA PaCa-2 (3D)
Concentration:

0.8, 4, 20, 100, 500 nM
Incubation Time:

24 h
Result:

Significantly inhibited the downstream phosphorylation of pERK and pS6.

In Vivo

Anti-cancer

BTX-6654 (10-50 mg/kg; i.p.; single dose; 2-24 h) demonstrates dose-proportional plasma and tumor exposure and effectively induces intratumoral SOS1 degradation and reduced pERK levels in NCI-H358 xenograft mouse models^[1].
BTX-6654 (2-10 mg/kg; i.p.; twice daily; 28 days) exhibits significant, dose-dependent tumor growth inhibition in NCI-H358 and MIA PaCa-2 xenograft models^[1].
BTX-6654 (10 mg/kg; i.p.; twice daily; 30 days) in combination with Sotorasib (HY-114277) (10 mg/kg; p.o.; once daily) or Trametinib (HY-10999) (0.125 mg/kg; p.o.; twice daily) demonstrates significant synergistic tumor growth inhibition in MIA PaCa-2 xenograft models^[1].

MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model:

BALB/c nude mice (6-8 weeks old, female) were subcutaneously inoculated with NCI-H358 cells in the right flank^[1]
Dosage:

10, 50 mg/kg
Administration:

i.p.; single dose; 2, 8, 24 h
Result:

Downregulated SOS1 and pERK proteins in histology.

Animal Model:

BALB/c nude mice (6-8 weeks old, female) were subcutaneously inoculated with NCI-H358 cells or MIA PaCa-2 cells in the right flank^[1]
Dosage:

2, 10 mg/kg
Administration:

i.p.; twice daily; 28 days
Result:

Inhibited tumor growth in a dose-dependent manner.
No significant effect on animal body weight.

Animal Model:

BALB/c nude mice (6-8 weeks old, female) were subcutaneously inoculated with xMIA PaCa-2 cells in the right flank^[1]
Dosage:

10 mg/kg (+ 10 mg/kg Sotorasib or 0.125 mg/kg Trametinib)
Administration:

i.p.; twice daily; 30 days
Result:

A trend toward profound tumor regression was observed in the combination therapy group.

Related Protocols :

Chemical Information

Molecular Weight 940.04
Formula C₅₀H₅₇F₄N₉O₅
SMILES

FC(F)(F)C1=C(C)C([C@@H](C)NC2=NN=C(C)C3=CC=C(N4CCN(C(C5CCN(C(CCN6CCC(C7=CC(CN(C8CCC(NC8=O)=O)C9=O)=C9C=C7F)CC6)=O)CC5)=O)CC4)C=C32)=CC=C1
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.

Purity & Documentation

Select Batch:

Purity: 99.98%

Assay: 99.98%

ee.: 99.98%

Data Sheet (276 KB)
SDS (252 KB)
- Français - FR (252 KB)
- Deutsch - DE (252 KB)
- Norwegian - NO (252 KB)
- Español - ES (252 KB)
- Swedish - SV (252 KB)
- Italian - IT (252 KB)
- Korean - KR (252 KB)
- Portuguese - PT (252 KB)
COA (2659 KB)
Elemental Analysis Report (2659 KB)
HNMR (2659 KB)
CNMR (2659 KB)
RP-HPLC (2659 KB)
NP-HPLC (2659 KB)
MS (2659 KB)
LCMS (2659 KB)
IR (2659 KB)
GC (2659 KB)
OR (2659 KB)
SDS-PAGE (2659 KB)
SEC-HPLC (2659 KB)
Other Report (2659 KB)
Handling Instructions (2659 KB)

References

[1]. Begovich K, et al. Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth. Molecular cancer therapeutics. 2024 Apr 02;23(4):407-420. [Content Brief]

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BTX-6654

All PROTACs Isoforms

All ERK Isoforms

All p38 MAPK Isoforms