Background:

IC50: 21/ 13 nM for mTOR/DNA-PK

CC-115 is a inhibitor of mTOR/DNA-PK.

The mammalian target of rapamycin (mTOR) kinase is a key mediator of the phosphoinositide 3-kinase /protein kinase B (AKT pathway). The DNA-dependent protein kinase (DNA-PK) is a critical component of the DNA repair machinery governings the response to DNA damage, which serves to maintain genome integrity.

In vitro: Previous study found that the proliferation induced by CD40(+) interleukin-21 stimulation could be completely blocked by CC-115, and CD40-mediated resistance to fludarabine and venetoclax could also be reverted by CC-115. Moreover, BCR-mediated signaling was blocked by CC-115 and in CLL samples from patients with acquired resistance to idelalisib treatment [1].

In vivo: Preclinical studies showed that CC-115 had good in vivo PK profiles across multiple species with 53%, 76%, and around100% oral bioavailability in mouse, rat, and dog, respectively [2].

Clinical trial: Clinical efficacy of CC-115 was studied in 8 patients with relapsed/refractory CLL/small lymphocytic lymphoma harboring ATM deletions/mutations. Results showed that all but one patient had a decrease in lymphadenopathy, leading to 1 IWCLL partial response (PR) and 3 PRs with lymphocytosis. These early promising clinical activity suggested that CC-115 might be developed further for treatment of CLL [1].

参考文献:
[1] Thijssen R,et al.  Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood.2016 Jul 28;128(4):574-83.
[2] Mortensen DS, et al.  Optimization of a Series of Triazole Containing Mammalian Target of Rapamycin (mTOR) Kinase Inhibitors and the Discovery of CC-115. J Med Chem. 2015 Jul 23;58(14):5599-5608.