LXH254
CAS No. : 1800398-38-2

LXH254
Cat. No. : CS-0043317
M. Wt. : 502.49
Size Stock Price Quantity Add to Cart Quotation Online
5mg In-stock USD 250.0
10mg In-stock USD 390.0
25mg In-stock USD 680.0
50mg In-stock USD 1200.0
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  • Data Sheet

  • Introduction

  • SDS

  • COA & Spectra

Name: LXH254; 
Cat. No. : CS-0043317
CAS No. : 1800398-38-2
Formula: C25H25F3N4O4
M. Wt. : 502.49
Solubility: DMSO : 100 mg/mL (ultrasonic)

Activity:

LXH254 is a potent, selective, orally active, type II BRAF and CRAF inhibitor, with IC50 values of 0.072 and 0.21 nM against CRAF and BRAF, respectively[2]. IC50 & Target: CRAF, BRAF[1] In Vitro: LXH254 (Compound A) is an adenosine triphosphate (ATP)-competitive inhibitor of BRAF (also referred to herein as b-RAF or b-Raf) and CRAF (also referred to herein as c-RAF or c- Raf) protein kinases. Throughout the present disclosure, LXH254 is also referred to as a c-RAF (or CRAF) inhibitor or a C-RAF/c-Raf kinase inhibitor. In cell-based assays, LXH254 has demonstrated anti-proliferative activity in cell lines that contain a variety of mutations that activate MAPK signaling. Moreover, LXH254 is a Type 2 ATP -competitive inhibitor of both B-Raf and C-Raf that keeps the kinase pocket in an inactive conformation, thereby reducing the paradoxical activation seen with many B-Raf inhibitors, and blocking mutant RAS-driven signaling and cell proliferation[1].
LXH254 (0-10 µM, 1 h) inhibits both monomeric and dimeric RAF and promotes RAF dimer formation[2].
LXH254 has reduced ability to suppress MAPK signaling driven by ARAF and further that the contribution of ARAF to MAPK signaling increases in the absence of CRAF expression[2].
LXH254 shows more sensitivity when cells lack ARAF[2]. In Vivo: Treatment with LXH254 (Compound A) generates tumor regression in several KRAS-mutant models including the NSCLC-derived Calu-6 (KRAS Q61K) and NCI-H358 (KRAS G12C). LXH254 exhibits efficacy in numerous MAPK-driven human cancer cell lines and in xenograft tumors representing model tumors harboring human lesions in KRAS, NRAS and BRAF oncogenes[1].
LXH254 shows significant antitumor activity in models harboring BRAF mutations either alone or coincident with either activated NRAS or KRAS, and RAS mutants lacking ARAF are more sensitive to LXH254[2].

Protocol:

Animal Administration: 90% PEG400 + 10% Tween80[1]Mice[1]
SCID beige female tumor-bearing NCI-H358 mice, n=8 per group, are randomized into 3 groups 14 days post tumor cell inoculation with an average tumor volume range of 259.44- 262.47mm3. Animals are administered an oral dose of either vehicle, LXH254 at 30mg/kg or 200mg/kg daily for 14 consecutive days at a dosing volume of 10 mL/kg of animal body weight during course of treatment. Tumor volumes are measured by digital caliper 3 times a week and body weights of all animals are recorded through the course of treatment.
Female nude tumor bearing Calu6 mice, n=6 per group are randomized into treatment groups on day 17 following tumor implantation, when the average tumor volume is 180 mm3. Treatments with LXH254 are initiated on Day 17 and continued for 16 days. Dosing volume is 10 mL/kg. Tumor volumes are collected at the time of randomization and twice weekly thereafter for the study duration.
Nude female mice tumor bearing NCI-H358, n=8 per group, are randomized into 2 groups with an average tumor volume range of 275.74 mm3. Animals are administered an oral dose of either vehicle or LXH254 at 100 mg/kg daily for 14 consecutive days at a dosing volume of 10 mL/kg of animal body weight during course of treatment. Tumor volumes are measured by digital caliper 3 times a week and body weights of all animals are recorded through the course of treatment[1].

References:

CAPONIGRO, Giordano, et al. THERAPEUTIC COMBINATIONS COMPRISING A RAF INHIBITOR AND A ERK INHIBITOR. WO 2018051306 A1 20180322

Kelli-Ann Monaco, et al. LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors. Clin Cancer Res. 2021 Apr 1;27(7):2061-2073.

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