Forodesine (BCX-1777 freebase) (Synonyms: BCX-1777, Immucillin H)

Forodesine(BCX-1777 freebase; Immucillin-H) is an orally bioavailable PNP inhibitor with picomolar potency; induces apoptosis, mainly in T cells.IC50 value:Target: PNP inhibitorForodesine and ara-G cytotoxicities were higher in T-cell acute lymphoblastic leukemia (T-ALL) samples than in B-cell precursor (BCP)-ALL and acute myeloid leukemia (AML) samples. Resistance to forodesine did not preclude ara-G sensitivity and vice versa, indicating that both drugs rely on different resistance mechanisms [1]. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation [2]. after 48 hours of treatment with forodesine there was a slight dGTP increase in 5T33MM and RPMI-8226 MM cells associated with partial inhibition of proliferation and a limited induction of apoptosis [3]. In the presence of 10 μM deoxyguanosine, forodesine effectively inhibited the growth of CEM cells but not that of CEM/ara-G cells [4].

[1]. Homminga I, et al. In vitro efficacy of forodesine and nelarabine (ara-G) in pediatric leukemia. Blood. 2011 Aug 25;118(8):2184-90. [2]. Ogura M, et al. Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Cancer Sci. 2012 Jul;103(7):1290-5. [3]. Bieghs L, et al. The effects of forodesine in murine and human multiple myeloma cells. Adv Hematol. 2010;2010:131895. [4]. Yamauchi T, et al. A nelarabine-resistant T-lymphoblastic leukemia CCRF-CEM variant cell line is cross-resistant to the purine nucleoside phosphorylase inhibitor forodesine. Anticancer Res. 2014 Sep;34(9):4885-92.