Amuvatinib, also known as MP-470, is an orally bioavailable synthetic carbothioamide with potential antineoplastic activity. Multitargeted receptor tyrosine kinase inhibitor MP470 binds to mutant forms of the stem cell factor receptor (c-Kit; SCFR), inhibiting clinically relevant mutants of this receptor tyrosine kinase that may be associated with resistance to therapy. In addition, MP470 inhibits activities of other receptor tyrosine kinases, such as c-Met, Ret oncoprotein, and mutant forms of Flt3 and PDGFR alpha, which are frequently dysregulated in variety of tumors.

Product information

CAS Number: 850879-09-3

Molecular Weight: 447.51

Formula: C23H21N5O3S

Synonym:

HPK 56

HPK-56

HPK56

MP470

MP 470

Amuvatinib

Related CAS Number:

1055986-67-8 (Amuvatinib hydrochloride)

Chemical Name: N-(benzo[d][1, 3]dioxol-5-ylmethyl)-4-(benzofuro[3, 2-d]pyrimidin-4-yl)piperazine-1-carbothioamide.

Smiles: S=C(NCC1C=C2OCOC2=CC=1)N1CCN(CC1)C1=NC=NC2=C1OC1=CC=CC=C12

InChiKey: FOFDIMHVKGYHRU-UHFFFAOYSA-N

InChi: InChI=1S/C23H21N5O3S/c32-23(24-12-15-5-6-18-19(11-15)30-14-29-18)28-9-7-27(8-10-28)22-21-20(25-13-26-22)16-3-1-2-4-17(16)31-21/h1-6,11,13H,7-10,12,14H2,(H,24,32)

Technical Data

Appearance: Solid Power

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

Solubility: DMSO: 32 mg/mL(71.5 mM). Water: Insoluble.

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:

The hydrochloride salt of MP-470 also inhibits several mutants of c-Kit, including c-KitD816V, c-KitD816H, c-KitV560G, and c-KitV654A, as well as a Flt3 mutant (Flt3D835Y) and two PDGFRα mutants (PDGFRαV561D and PDGFRαD842V), with IC50 of 10 nM to 8.4 μM. MP-470 potently inhibits the proliferation of OVCAR-3, A549, NCI-H647, DMS-153, and DMS-114 cells, with IC50 of 0.9 μM–7.86 μM. MP-470 also inhibits c-Kit and PDGFRα, with IC50 values of 31 μM and 27 μM, respectively. MP-470 demonstrates potent cytotoxicity against MiaPaCa-2, PANC-1, and GIST882 cells, with IC50 of 1.6 μM to 3.0 μM. MP-470 also binds to and inhibits several c-Kit mutants, including c-KitK642E, c-KitD816V, and c-KitK642E/D816V. In MDA-MB-231 cells, MP-470 (1 μM) inhibits tyrosine phosphorylation of AXL. In LNCaP and PC-3, but not DU145 cells, MP-470 exhibits cytotoxicity with IC50 of 4 μM and 8 μM, respectively, and induces apoptosis at 10 μM. In LNCaP cells, MP-470 (10 μM) elicits G1 arrest and decreases phosphorylation of Akt and ERK1/2. In SF767 cells, MP-470 (10 μM) inhibits c-Met phosphorylation and sensitizes cells to radiation. In combination with radiation, MP-470 (10 μM) inhibits glycogen synthase kinase (GSK)3β activity, induces apoptosis, and disrupts the repair of dsDNA breaks probably through suppression of Rad51.

In Vivo:

In mice xenograft models of HT-29, A549, and SB-CL2 cells, MP-470 (10 mg/kg–75 mg/kg via i.p. or 50 mg/kg–200 mg/kg via p.o.) inhibits tumor growth. In mice bearing LNCaP xenograft, MP-470 (20 mg/kg) combined with Erlotinib significantly induces tumor growth inhibition (TGI).

References:

1. Bearss DJ, et al. US Patent, US/2008/0226747.
2. Hurley LH, et al. World Patent, WO/2005/037825.
3. Mahadevan D, et al. Oncogene, 2007, 26(27), 3909-3919.
4. Qi W, et al. BMC Cancer, 2009, 9, 142.
5. Welsh JW, et al. Radiat Oncol, 2009, 4, 69.
6. Zhao H, et al. Radiother Oncol, 2011, 101(1), 59-65.
7. P A Baxter, et al. Cancer Chemother Pharmacol . 2011 Apr;67(

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