TH588

Biological Activity

TH588 a first-in-class nudix hydrolase family inhibitor that potently and selectively engages and inhibits the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitor binds in the active site of MTH1.

MTH1 inhibitor TH588 is highly selective towards MTH1, with no relevant inhibition of other members of the nudix protein family or a panel of 87 enzymes, GPCRs, kinases, ion channels and transporter. TH588 also induces DNA damage and triggers an ATM-p53-mediated death response and DNA repair in U2OS cells. TH588 has been shown to selectively kill a variety of cancer cell lines and with in vivo activity shown for TH588 in SW480 colorectal and MCF7 breast tumour xenografts.

In mice bearing SW480 colorectal or MCF7 breast tumor xenografts, TH588 (30 mg/kg s.c.) reduces tumor growth via MTH1 inhibition. In mice carrying patient with BRAFV600E mutated xenografts, TH588 (30 mg/kg s.c.) also causes a reduced tumor growth rate.

Protocol

Cell Experiment
Cell lines
Preparation method
Concentrations
Incubation time

Animal Experiment
Animal models	SCID mice bearing SW480 xenografts or MCF-7 xenografts; NOD-SCID IL2Rγnull (NOG) mice bearing patient with BRAFV600E mutated xenografts
Formulation	2% DMSO, 10% ethanol, 10% cremaphore, 10% Tween 80, 68% PBS; 10% N-methylpyrrilidone, 90% PEG300
Dosages	30 mg/kg, once daily
Administration	s.c.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

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 resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 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 resveratrol of 11.2 mg/kg.

Chemical Information

References

Development and validation of method for TH588 and TH287, potent MTH1 inhibitors and new anti-cancer agents, for pharmacokinetic studies in mice plasma.
Saleh A, et al. J Pharm Biomed Anal. 2015 Feb;104:1-11. PMID: 25459754.

MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool.
Gad H, et al. Nature. 2014 Apr 10;508(7495):215-21. PMID: 24695224.