2748337-86-0

AZ12601011 is an orally active, selective TGFBR1 kinase inhibitor with an IC50 of 18 nM and a Kd of 2.9 nM. AZ12601011 inhibits phosphorylation of SMAD2 via selectively inhibiting ALK4, TGFBR1, and ALK7. AZ12601011 inhibits mammary tumor growth [1].

AZ12601011 is an orally activesubtype-selective TGF-β type I receptors active site inhibitor (active-site affinity: ALK4/5/6 Kd = 2.6/2.9/42 nMALK1/2/3 Kd = 40/15/40 μM) th at prevents ALK4/5/7-mediated Smad2but not ALK1/2/3/6-mediated Smad1phosphorylation (10 μM; NIH3T3 expressing respective constitutively active receptors). AZ12601011 inhibits 4T1 murine mammary carcinoma growth in cultures (IC50 = 400 nM) and in vivo (50 mg/kg bid. po. mice). AZ12601011 also causes heart valve lesions and physeal dysplasia in rats (150 mg/kg/day po. for 7 days)consistent with a critical role of ALK5 in maintaining the integrity of heart valve and physis.

ALK4; ALK7

[1] Spender LC, et al. Preclinical Evaluation of AZ12601011 and AZ12799734, Inhibitors of Transforming Growth Factor βSuperfamily Type 1 Receptors. Mol Pharmacol. 2019 Feb;95(2):222-234. DOI:10.1124/mol.118.112946