Mps1 (IC50 = 182 nM); CK2 (IC50 = 5.7 μM); MELK (IC50 = 6.01 μM); NEK6 (IC50 = 6.02 μM)

NMS-P715 has an IC50 of 182 nM, making it a selective inhibitor of MPS1. With IC50 values less than 5 μM, NMS-P715 does not inhibit any other kinases and is extremely selective for MPS1. Only three kinases—MELK, NEK6, and CK2—have inhibition at IC50 values smaller than 10 μM. With an EC50 of 65 nM, NMS-P715 facilitates extensive spindle assembly checkpoint (SAC) coverage. NMS-P715 (1 μM) causes aneuploidy, speeds up mitosis, and prevents HCT116 cells from proliferating in U2OS cells that overexpress YFP-α-tubulin. NMS-P715 (0.5, 1 μM) influences the ubiquitination of CDC20 and the stability of the mitotic checkpoint complex (MCC) [1]. NMS-P715 (1 μM) in pancreatic ductal adenocarcinoma (PDAC) cell lines causes apoptosis and bypasses the spindle assembly checkpoint. Additionally, NMS-P715 (0-25 μM) specifically prevents PDAC cell proliferation [2].

In nude mice implanted subcutaneously with human tumor cell xenografts, NMS-P715 (10 mg/kg) showed good pharmacokinetic characteristics and 37% oral bioavailability. In the A2780 ovarian cancer xenograft model, NMS-P715 (90 mg/kg, oral) was well tolerated; there were no indications of weight loss or any overt harm. Oral NMS-P715 (100 mg/kg) reduces tumor growth in the A375 melanoma xenograft model by about 43% [1].

[1]. Targeting the mitotic checkpoint for cancer therapy with NMS-P715, an inhibitor of MPS1 kinase. Cancer Res. 2010 Dec 15;70(24):10255-64.
[2]. Selective inhibition of pancreatic ductal adenocarcinoma cell growth by the mitotic MPS1 kinase inhibitor NMS-P715. Mol Cancer Ther. 2014 Feb;13(2):307-315

MPS1 kinase is a key regulator of spindle assembly checkpoint (SAC), a mechanism necessary for the proper alignment and separation of chromosomes during cell mitosis. Studies have found that MPS1 kinase is abnormally highly expressed in a variety of human tumors and is essential for tumor cell proliferation. This article reports the identification and characterization of NMS-P715, a selective and orally bioavailable small molecule inhibitor of MPS1. NMS-P715 selectively inhibits cancer cell proliferation with little effect on normal cells. NMS-P715 accelerates mitosis and affects the localization of kinetochore components, resulting in a large number of aneuploidies and cell death in a variety of tumor cell lines and inhibiting tumor growth in preclinical cancer models. Inhibition of SAC may be a promising new approach to selectively target cancer cells. [1]

---

Most solid tumors, including pancreatic ductal adenocarcinoma (PDAC), exhibit structural and numerical chromosomal instability (CIN). Although chromosomal instability (CIN) is often considered a driver of tumor progression and drug resistance, it also reduces cell viability and constitutes a vulnerability that can be exploited for therapeutic purposes. Spindle assembly checkpoints (SACs) ensure the proper connection of chromosomes to microtubules, thereby minimizing chromosome segregation errors. Many tumors exhibit upregulation of SAC components, such as MPS1, which may help control CIN within a viable range. Previous studies have shown that inhibiting MPS1 using the small molecule NMS-P715 can limit tumor growth in xenograft models. In cancer cell lines, NMS-P715 induces cell death, which is associated with impaired SAC function and increased chromosome segregation errors. While normal cells appear to be more resistant, its effects on stem cells, which are dose-limiting toxicity targets for most chemotherapeutic drugs, have not been investigated. High expression of 70 genes, including MPS1 (CIN70), can serve as a surrogate marker of CIN and predicts lower survival rates in patients with various tumor types. Our new findings indicate that the degree of CIN70 upregulation varies significantly among different PDAC tumors, with higher CIN70 gene expression associated with worse prognosis. We identified a subset of 25 genes (PDAC CIN25) whose overexpression was closely associated with poor survival, including MPS1. In vitro experiments showed that NMS-P715 inhibited the growth of human and mouse PDAC cells, while adipose-derived human mesenchymal stem cells were relatively tolerant and maintained chromosomal stability after exposure to NMS-P715. These studies suggest that NMS-P715 may have a good therapeutic index and warrants further investigation into MPS1 inhibition as a new PDAC treatment strategy. [2]

C35H42N8O3

622.759787082672

622.338

C, 67.50; H, 6.80; N, 17.99; O, 7.71

1202055-34-2

1202055-34-2

44556163

White to off-white solid powder

1.3±0.1 g/cm3

1.676

3.69

3

8

9

46

1010

0

O=C(C1C=CC(=C(C=1)OC)NC1=NC=C2C(C3=C(C(C(NC4C(=CC=CC=4CC)CC)=O)=NN3C)CC2)=N1)NC1CCN(C)CC1

WGZYFFJOGZFXBF-UHFFFAOYSA-N

InChI=1S/C35H42N8O3/c1-6-21-9-8-10-22(7-2)29(21)39-34(45)31-26-13-11-24-20-36-35(40-30(24)32(26)43(4)41-31)38-27-14-12-23(19-28(27)46-5)33(44)37-25-15-17-42(3)18-16-25/h8-10,12,14,19-20,25H,6-7,11,13,15-18H2,1-5H3,(H,37,44)(H,39,45)(H,36,38,40)

N-(2,6-diethylphenyl)-8-[2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]anilino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide

CHEMBL1808340; N-(2,6-diethylphenyl)-8-[2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]anilino]-1-methyl-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide; Desfluoro-NMS-P715; NMSP-715; SCHEMBL1559206;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~2 mg/mL (~2.96 mM)

Solubility in Formulation 1: 3.33 mg/mL (4.92 mM) in 0.5% CMC/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

 (Please use freshly prepared in vivo formulations for optimal results.)