LOXO-195 is a potent and selective, next-generation TRK inhibitor, with IC50 values of 0.6±0.1 nM, <2.5 nM for TRKA and TRKC, respectively. LOXO-195 achieves low nanomolar inhibitory activity against TRKA G595R, TRKC G623R, and TRKA G667C, with IC50s ranging from 2.0-9.8 nM. LOXO-195 demonstrates potent inhibition of cell proliferation in TRK fusion-containing KM12, CUTO-3, and MO-91 cell lines (IC50≤5 nM).
In diverse TRK fusion mouse models, LOXO-195 also causes inhibition of tumor growth relative to vehicle at all doses in four TRKA-dependent tumor models, superior to first generation TRK inhibitors, without significant toxicity.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO: ≥ 55 mg/mL (Need ultrasonic)|
A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.
Drilon A, et al. Cancer Discov. 2017 Sep;7(9):963-972. PMID: 28578312.
|Related Trk Products|
LOXO-101 sulfate is an oral potent and selective ATP-competitive inhibitor of tropomyosin receptor kinases (TRK).
LOXO-101 is a potent, ATP competitive TRK inhibitor with IC50s in low nanomolar range for inhibition of all TRK family members in binding and cellular assays, with 100x selectivity over other kinases, with 2 to 20 nM cellular potency against the TRKA, TRKB, and TRKC kinases.
ANA-12 is a selective TrkB antagonist with Kd of 10 nM and 12 μM for the high and low affinity sites, respectively.
GW441756 is a potent, selective inhibitor of TrkA with IC50 of 2 nM, with very little activity to c-Raf1 and CDK2.
GNF-5837 is a potent pan-Trk inhibitor which display antiproliferative effects in cellular Ba/F3 assays (IC50 values are 7, 9 and 11 nM for cells containing the fusion proteins Tel-TrkC, Tel-TrkB and Tel-TrkA, respectively.
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