1-(4-(4-(2-(isopropylsulfonyl)phenylamino)-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-3-methoxyphenyl)piperidin-4-ol

Definition

ChEBI: 1-[3-methoxy-4-[[4-(2-propan-2-ylsulfonylanilino)-1H-pyrrolo[2,3-b]pyridin-6-yl]amino]phenyl]-4-piperidinol is a member of piperidines.

Biological Activity

mps1-in-1 is a selective mps1 (monopolar spindle 1) kinase inhibitor with ic50 value of 367 nm.mps1 (monopolar spindle 1 kinase) is a crucial part of the spindle assembly checkpoint. it facilitates the formation of c-mad2 (closed mad2) conformer and the mcc (mitotic checkpoint complex) assembly, involved in the maintenance of chromosomal stability and tumor growth.mps1-in-1 abolishes the sac (spindle assembly checkpoint) function. in u2os cells, dose-dependent treatment of mps1-in-1 decreases the time spent in mitosis with almost 100% cells starting anaphase in 20 minutes. in contrast, just 10% of dmso-treated cells starting anaphase in the same period. acceleration of mitosis kinetics in mps1-in-1 treated cells affects genomic stability and causes aneuploidy. in addition, mps1-in-1 treated cells shows decrease in kinetochore-bound mad2 by 80%. mps1-in-1–treated cells spent roughly 40% less time in mitosis as compared to dmso-treated cells. moreover, mps1-in-1 disrupts the kinase activity of aurora b. mps1-in-1 treatment lead to decrease in the phosphorylation status of aurora b at thr232 in a dose-dependent manner. furthermore, mps1-in-1 increases multipolar cell divisions and decreases cell viability.

in vitro

Mps1-IN-1 is a potent, selective and ATP-competitive Mps1 kinase inhibitor, with an IC ₅₀ and a K _d of 367 nM and 27 nM. It also has high affinity for ALK, and LTK, with K _d s of 21 and 39 nM, respectively, but shows little or no inhibition on other 352 member kinases. Mps1 -IN-1 (5, 10 μM) induces bypass of a checkpoint-mediated mitotic arrest in U2OS cells.

target

Mps1 367 nM (IC 50 )

Mps1 27 nM (Kd)

ALK 21 nM (Kd) < /p>

LTK 29 nM (Kd)

PYK2 280 nM (Kd)

FAK < /span> 440 nM (Kd)

IGF1R 750 nM (Kd)

INSR 470 nM (Kd)

CLK1 1900 nM (Kd) < /td>

ERK2 2900 nM (Kd)

INSRR 1200 nM (Kd)

TNK1 < /p> 2600 nM (Kd)

TNK2 3100 nM (Kd)

GAK 1100 nM (Kd)

References

kwiatkowski n, jelluma n, filippakopoulos p et al. small-molecule kinase inhibitors provide insight into mps1 cell cycle function. nat chem biol. 2010 may;6(5):359-68.