BI-3406

Description

APIM050400: BI-3406 (BI3406), Potent and Selective Inhibitor of the Interaction between KRAS and SOS1

CAS No.: 2230836-55-0
IUPAC/Chemical Name: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)quinazolin-4-amine
Molecular Formula: C₂₃H₂₅F₃N₄O₃
Molecular Weight: 462.46
Purity: >99.5%
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO (37.0 mg/ml, 80 mM)
Storage: Store at 0 °C (short term), -20 °C (long term), Desiccated

Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

KRAS functions as a molecular switch, cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce extracellular signals via cell-surface receptors. KRAS signaling occurs through engagement with effector proteins that orchestrate intracellular signaling cascades regulating tumor cell survival and proliferation. Mutations in the KRAS gene occur in approximately one of seven of all human cancers. Up to 90% of pancreatic tumors bear activating KRAS mutations. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF–MEK–ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. BI-3406 (CAS No. 2230836-55-0) is a highly potent, selective, and orally bioavailable inhibitor of the interaction between KRAS and Son of Sevenless 1 (SOS1) with an IC₅₀ of 6 nM. BI-3406 potently reduces the formation of GTP-loaded KRAS, and inhibits MAPK pathway signaling. BI-3406 (BI3406) binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS.[2]

BI-3406 binds to SOS1 and thereby blocks protein-protein interaction with RAS-GDP. Moreover, it is the first example of an orally bioavailable SOS1-KRAS interaction inhibitor that reduces RAS-GTP levels and curtails MAPK pathway signaling. It also reduces cell proliferation of a large fraction of KRAS G12C-driven and non-G12C-driven cancers. In addition, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances the sensitivity of KRAS-dependent cancers to MEK inhibition.[2]

BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, elucidates its mode of action both in vitro and in vivo. BI-3406 enhances the extent and duration of MAPK pathway inhibition upon the combination with a MEK or KRAS G12C inhibitor. Thus, it is able to counteract adaptive resistance. All in all, this highlights SOS1 inhibition as a promising combination option for MAPK pathway and direct KRAS inhibitors.[2]

Target: KRAS-SOS1

IC₅₀: 6 nM

In Vitro: BI-3406 is an inhibitor of the interaction between KRAS and its Guanine Nucleotide Exchange Factor (GEF) SOS1. BI-3406 does not block the interaction of KRAS with SOS2 but elicits activity on a broad panel of KRAS oncogenic variants, including all major G12 and G13 oncoproteins. Down-modulation of this signaling cascade by BI-3406 in KRAS G12 or G13 mutant cells effectively limits cell proliferation.[1]

What is the solubility of BI-3406 in vitro?
100 mg/mL in DMSO (Need ultrasonic), 100 mg/mL in ethanol (Need ultrasonic)

What is the solubility of BI-3406 in vivo?
1. Solvent: DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order; solubility ≥ 2.5mg/mL.
2. DMSO and 20% SBE-β-CD in salin
Please add 10% DMSO and 90% (20% SBE-β-CD in saline) in order; solubility 2.5 mg/mL (need ultrasonic).
3. DMSO and corn oil
Please add 0% DMSO and 90% corn oil in order, solubility ≥ 2.5 mg/mL.
4. EtOH, PEG300, Tween-80, and saline
Please add 10% EtOH, 40% PEG300, 5% Tween-80, and 45% saline in order, solubility ≥ 2.5 mg/mL.
5. EtOH and 20% SBE-β-CD in saline
Please add 10% EtOH and 90% (20% SBE-β-CD in saline) in order, solubility ≥ 2.5 mg/mL.
6. EtOH and corn oil
Please add 10% EtOH and 90% corn oil in order, solubility ≥ 2.5 mg/mL.

Reference:
[1]. Hofmann, M. H. et al. “Abstract PL06-01: Discovery of BI-3406: A potent and selective SOS1::KRAS inhibitor opens a new approach for treating KRAS-driven tumors” Mol. Cancer Ther. 2019, PL06-01.
[2]. Hofmann, M. H. et al. “BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition” Cancer Discov. 2021, 11, 142-157.
[3]. Kessler, D. et al. “Targeting Son of Sevenless 1: The pacemaker of KRAS (BI-3406)” Curr. Opin. Chem. Biol. 2021, 62, 109-118.

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Additional information

Size	10 mg, 100 mg, 5 mg, 50 mg

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