Uses
Samotolisib (LY3023414) potently and selectively inhibits class I PI3K isoforms, DNA-PK, and mTORC1/2 with IC50s of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. Samotolisib potently inhibits mTORC1/2 at low nanomolar concentrations[1][2].
Biological Activity
ly3023414 is an atp competitive inhibitor of the class i pi3k isoforms, mtor and dna-pk.the phosphoinositide-3 kinase (pi3k)/akt/mammalian target of rapamycin (mtor) pathway is one of the most frequently altered pathways in cancer cell growth and survival.
in vitro
in biochemical testing against approximately 266 kinases, ly3023414 was found to potently and selectively inhibit class i pi3k isoforms, mtorc1/2, as well as dna-pk at low concentrations. in addition, inhibition of pi3k/akt/mtor signaling by ly3023414 led to g1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel [1].
in vivo
ly3023414 showed high bioavailability and dose-dependent dephosphorylation of pi3k/akt/mtor pathway downstream substrates for 4 to 6 hours, indicating ly3023414's half-life of 2 hours. moreover, equivalent total daily doses of ly3023414 given either once or twice daily could inhibit tumor growth to the similar extents in multiple xenograft models, demonstrating intermittent target inhibition was sufficient for antitumor activity [1].
target
| Target | Value |
class I PI3K isoforms
() |
mTOR kinase
() |
DNA-PK
() |
IC 50
64.9, 42.1, 10.6, and 19.1 nm for akt1(pt308), akt1 (ps473), p70s6(pt389), and s6rp(ps240/242), respectively.
References
[1] smith mc,mader mm,cook ja,et al. characterization of ly3023414, a novel pi3k/mtor dual inhibitor eliciting transient target modulation to impede tumor growth. mol cancer ther.2016 oct;15(10):2344-2356.
