TJ-M2010-5

Biological Activity

TJ-M2010-5 is a MyD88 inhibitor that binds to the TIR domain of MyD88 to interfere with its homodimerization, and the TLR/MyD88 signal pathway. TJ-M2010-5 inhibited MyD88 homodimerization in transfected HEK293 cells in a concentration-dependent manner and suppressed MyD88 signaling in LPS-responsive RAW 264.7 cells in vitro. 

In a 10-week CAC mouse model (n = 30 per group), TJ-M2010-5 treatment statistically significantly reduced AOM/DSS-induced colitis and completely prevented CAC development with less related body mass loss, resulted in 0% mortality of treated mice (compared with 53% mortality of control mice), decreased cell proliferation, and increased apoptosis in colon tissue. TJ-M2010-5 treatment also inhibited production of inflammatory cytokines and chemokines (TNF-α, IL-6,G-CSF, MIP-1β, TGF-β1, IL-11, IL-17A, IL-22 and IL-23) and infiltration of immune cells (macrophages, dendritic cells, neutropihls and CD(+)4 T cells) in colon tissues of mice.

Protocol (for reference only)

Cell Experiment
Cell lines	RAW 264.7 cells
Preparation method	RAW 264.7 cells were cultured in RPMI medium 1640. After stimulation with 100ng/mL of lipopolysaccharide (LPS) for six hours with 40 µM TJ-M2010-5 or vehicle one hour pretreatment, cells in individual wells were harvested for protein extraction.
Concentrations	40 µM
Incubation time	6 hours

Animal Experiment
Animal models	Female BalB/c mice (6–8 weeks old)
Formulation	vehicle (ddH2 O)
Dosages	50mg/Kg daily
Administration	i.p.

Chemical Information

Molecular Weight	406.54
Formula	C23H26N4OS
CAS Number	1357471-57-8
Solubility (25°C)	DMSO 90 mg/mL
Storage	4°C, protect from light, sealed

Conversion of different model animals based on BSA (PMID: 27057123)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

References

[1] Zeyang Li, et al. Front Pharmacol. TJ-M2010-5, a novel CNS drug candidate, attenuates acute cerebral ischemia-reperfusion injury through the MyD88/NF-κB and ERK pathway

[2] Huifang Yang, et al. J Cardiovasc Transl Res. TJ-M2010-5 Attenuates Severe Myocardial Ischemia/Reperfusion Injury in Heart Transplantation by Inhibiting MyD88 Homodimerization In Vivo

[3] Yalong Xie, et al. Chem Biol Interact. TJ-M2010-5, A self-developed MyD88 inhibitor, attenuates liver fibrosis by inhibiting the NF-κB pathway

[4] Wei Zhou, et al. Int Immunopharmacol. Hypothermic oxygenated perfusion combined with TJ-M2010-5 alleviates hepatic ischemia-reperfusion injury in donation after circulatory death

[5] Yan Miao, et al. Am J Transl Res. Inhibition of MyD88 by a novel inhibitor reverses two-thirds of the infarct area in myocardial ischemia and reperfusion injury

[6] Zhimiao Zou, et al. Int Immunopharmacol. TJ-M2010-5, a novel MyD88 inhibitor, corrects R848-induced lupus-like immune disorders of B cells in vitro

[7] Lin Xie, et al. J Natl Cancer Inst. Targeting of MyD88 Homodimerization by Novel Synthetic Inhibitor TJ-M2010-5 in Preventing Colitis-Associated Colorectal Cancer