LC-2, PROTACs for KRAS

LC-2 is the first PROTAC capable of degrading endogenous KRAS(G12C). It covalently binds KRASG12C with a MRTX849 warhead and recruits the E3 ligase VHL, inducing rapid and sustained KRASG12C degradation leading to suppression of MAPK signaling in both homozygous and heterozygous KRASG12C cell lines.

Product information

CAS Number: 2502156-03-6

Molecular Weight: 1132.78

Formula: C59H71ClFN11O7S

Chemical Name: (2S,4R)-1-[(2S)-2-(3-{3-[(2S)-2-({[7-(8-chloronaphthalen-1-yl)-4-[(3S)-3-(cyanomethyl)-4-(2-fluoroprop-2-enoyl)piperazin-1-yl]-5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-2-yl]oxy}methyl)pyrrolidin-1-yl]propoxy}propanamido)-3,3-dimethylbutanoyl]-4-hydroxy-N-{[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl}pyrrolidine-2-carboxamide

Smiles: CC1N=CSC=1C1C=CC(CNC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC(=O)CCOCCCN2CCC[C@H]2COC2=NC3CN(CCC=3C(=N2)N2C[C@H](CC#N)N(CC2)C(=O)C(=C)F)C2=CC=CC3=CC=CC(Cl)=C32)C(C)(C)C)=CC=1

InChiKey: ZCGQZLKPUVGCBQ-HLMPTVQRSA-N

InChi: InChI=1S/C59H71ClFN11O7S/c1-37(61)56(76)71-27-26-70(32-42(71)19-22-62)54-45-20-25-69(48-14-7-11-40-10-6-13-46(60)51(40)48)34-47(45)65-58(67-54)79-35-43-12-8-23-68(43)24-9-28-78-29-21-50(74)66-53(59(3,4)5)57(77)72-33-44(73)30-49(72)55(75)63-31-39-15-17-41(18-16-39)52-38(2)64-36-80-52/h6-7,10-11,13-18,36,42-44,49,53,73H,1,8-9,12,19-21,23-35H2,2-5H3,(H,63,75)(H,66,74)/t42-,43-,44+,49-,53+/m0/s1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO: 50 mg/mL (ultrasonic;warming; heat to 80°C); H2O: < 0.1 mg/mL

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

LC-2 induces degradation of endogenous KRASG12C in multiple KRAS mutant cancer cell (NCI-H2030, MIA PaCa-2, SW1573, NCI-H23 and NCI-H358 cells) with DC50s between 0.25 and 0.76 μM. LC-2-induced KRASG12C degradation occurs via a bona fide PROTAC mechanism. MIA PaCa-2, NCI-H23, and SW1573 cells are treated with 2.5 μM of LC-2 for 6, 24, 48, and 72 h. In all three cell lines, maximal KRAS degradation occurred within 24 h and was sustained up to 72 h. LC-2-induced (2.5 μM; 6-24 hours) KRAS G12C degradation modulates Erk signaling in homozygous and heterozygous KRAS mutant cell lines.

References:

1. De Vita E, et al. The Missing Link between (Un)druggable and Degradable KRAS. ACS Cent Sci. 2020;6(8):1281-1284. [2]. Bond MJ, et al. Targeted Degradation of Oncogenic KRASG12C by VHL-Recruiting PROTACs. ACS Cent Sci. 2020;6(8):1367-1375.

Products are for research use only. Not for human use.