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> Pathway Inhibitors>Protein Inhibitors>AZ82

Protein Inhibitors

AZ82 View larger

AZ82

AOB4872

CAS No: 1449578-65-7

 

Chemical Name: 5-Methyl-4-propyl-thiophene-2-carboxylic acid {1(R)-(pyrrolidin-3(R)-ylcarbamoyl)-2-[6-(3-trifluoromethoxy-phenyl)-pyridin-3-yl]-ethyl}-amide

AOBIOUS launched this product in 2015

CITATIONS - Publications That Use AOBIOUS Product

1) The EMBO Journal, 20 Nov 2020, 39(24):e103661

2) Sci Adv, 10(25):eadl6153, 19 Jun 2024

 

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QuantitymgUnit Price ($/mg or $/Unit)Final Price
15 $17.85 Total: $89.25
110 $15.12 Total: $151.20
125 $12.81 Total: $320.25
150 $10.92 Total: $546.00
1100 $9.45 Total: $945.00

Data sheet

Molecular FormulaC28H31F3N4O3S
Molecular Weight560.63
CAS Numbers1449578-65-7
Storage Condition0°C (short term), -20°C (long term), desiccated
SolubilityDMSO
Purity98% by HPLC
IUPAC/Chemical NameαR-[[(5-methyl-4-propyl-2-thienyl)carbonyl]amino]-N-(3R)-3-pyrrolidinyl-6-[3-(trifluoromethoxy)phenyl]-3-pyridinepropanamide
InChl KeyPMTLKNOARSHUJB-ZJSXRUAMSA-N
InChl CodeInChI=1S/C28H31F3N4O3S/c1-3-5-19-14-25(39-17(19)2)27(37)35-24(26(36)34-21-10-11-32-16-21)12-18-8-9-23(33-15-18)20-6-4-7-22(13-20)38-28(29,30)31/h4,6-9,13-15,21,24,32H,3,5,10-12,16H2,1-2H3,(H,34,36)(H,35,37)/t21-,24-/m1/s1
SMILES CodeO=C(N[C@@H]1CCNC1)[C@H](NC(C2=CC(CCC)=C(C)S2)=O)CC3=CC=C(C4=CC(OC(F)(F)F)=CC=C4)N=C3
References1) Godinho, S.A., and Pellman, D. Causes and consequences of centrosome abnormalities in cancer. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369(1650), 20130467 (2014).

2) Wu, J., Mikule, K., Wang, W., et al. Discovery and mechanistic study of a small molecule inhibitor for motor protein KIFC1. ACS Chem. Biol. 8(10), 2201-2208 (2013).

More info

Novel inhibitor of motor protein KIFC1

AZ82 is a small molecule inhibitor of the motor protein KIFC1 (also called HSET), which is a minus-end directed kinesin family motor (kinesin-14). PubMed+3PMC+3

Here are its key functional effects and how it works:

Function / EffectDetails
Target bindingAZ82 binds to the KIFC1/microtubule complex, not to KIFC1 alone or microtubules alone. 
Inhibition typeInhibits the microtubule-stimulated ATPase activity of KIFC1 in an ATP-competitive manner (blocks ATP binding) and microtubule-noncompetitive manner with respect to binding to microtubules. PubMed
PotencyHas an IC₅₀ ~ 300 nM under certain assay conditions (MT-stimulated ATPase).
Kᵢ ~ 43 nM. 
SelectivityLow inhibition (<~15%) of other kinesin motors (e.g., Eg5, KIF5B, KIF4A, etc.) at concentrations of ~5 µM, meaning AZ82 is fairly selective for KIFC1. 

Effects in Cells

What happens in cells, especially cancer cells, when AZ82 is used:

  • Centrosome declustering / multipolar spindles: Cancer cells often have amplified centrosomes (more than the normal two), which if left unchecked lead to multipolar spindles during mitosis. KIFC1 helps cluster these extra centrosomes into two poles (“pseudo-bipolar spindles”) so that mitosis can proceed relatively normally. AZ82 inhibits KIFC1, preventing the clustering, leading to multipolar spindles, which can cause mitotic errors and cell death. PubMed+2

  • Mitotic delay: Cells treated with AZ82 show delayed mitosis, because the spindle apparatus isn’t properly organized. 

  • Apoptosis or cell death: In cancer cells with extra centrosomes, AZ82 treatment leads to increased cell death (apoptosis) because mitosis fails (due to spindle abnormalities). ResearchGate

  • Effect depends on centrosome status: AZ82 has more dramatic effects in cells with centrosome amplification (e.g. certain breast cancer cells like BT-549) than in cells with normal centrosome numbers (e.g. HeLa, MCF-7). In the latter, effects are weaker or require higher concentrations. 

  • Interaction with other mitotic motor inhibitors: Inhibition of +-end directed kinesin Eg5 causes monopolar spindles. AZ82 can “rescue” or offset that effect in some experimental setups (i.e. co-treatment restores more bipolar spindle morphology). This suggests that KIFC1 and Eg5 exert opposing forces in spindle dynamics. 



Biological/Clinical Implications

  • Because many cancer cells rely on centrosome clustering via KIFC1 to survive (otherwise mitosis is fatal), AZ82 has been proposed as a way to selectively kill cancer cells having centrosome amplification while sparing normal diploid or non-amplified cells. PubMed+1

  • In soft tissue sarcoma, studies show that AZ82 can induce cellular senescence, altering cell cycle regulators, arresting cells in G2/M, increasing markers like p21/p53, etc. PMC

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