Ki = 1.6 nM for MCT1

AZD 3965 is a potent inhibitor of monocarboxylate transporter 1 (MCT1).

Inhibition of monocarboxylate transporter 1 (MCT1) is currently considered as a promosing therapeutic way to block lactate shuttling in tumor cells lacking monocarboxylate transporter 4.

In vitro: Previous study found that the in-vitro AZD3965 sensitivity varied and was highest in hypoxia. To further support that AZD3965 targeted MCT1, NCIH1048 cells were engineered to inducibly overexpress MCT1. It was found that when MCT1 was overexpressed, the EC50 of AZD 3965 against NCI-H1048 was increased from 0.14 to 10.5 nM, which was consistent with AZD3965 acting through MCT1 inhibition [1].

In vivo: COR-L103 xenograft studies were conducted to test whether the in-vitro effect of AZD3965 could be recapitulated in vivo. COR-L103 tumor-bearing mice were treated with AZD3965 at 100 mg/kg BID for 21 days. The pharmacokinetic analyses showed that AZD3965 at 100 mg/kg BID led to free concentrations of AZD3965 predicted to inhibit lactate transport. Moreover, AZD3965 treatment was able to reduce the growth of CORL103 tumors significantly, though tumor regression was not observed, which was consistent with AZD3965 only targeting the hypoxic fraction of the tumor [1].

Clinical trial: A phase I trial of AZD3965 in patients with advanced cancer is currently recruiting participants [2].

References:
[1] Polanski, R. ,Hodgkinson, C.L.,Fusi, A., et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin.Cancer.Res 20(4), (2014).
[2] https://clinicaltrials. gov/ct2/show/NCT01791595 term=AZD+3965&rank=1