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Questions And Answer

• Bioactivity

  Alectinib (CH5424802) is an efficient ALK inhibitor. Its IC50 is 1.9nM and it is sensitive to the L1196M mutant, which is highly selective for ALK than PF-02341066, NVP-TAE684 and PHA-E429.;

• Solubility

  In vitro (25 ° C): DMSO-2 mg/mL heating (4.14 mM); Water-<1 mg/mL (<1 mM); Ethanol-<1 mg/mL (<1 mM)
  In vivo (25 ° C): 30% PEG 400/0.5% Tween 80/5% propylene glycol-30 mg/mL.;

• In vitro

  Alteinib (CH5424802) can act on ALK and it is ATP-competitive, with a dissociation constant (KD) of 2.4 nM. CH5424802 has a strong inhibitory effect on ALK and L1196M. The Ki is 0.83 and 1.56 nM, respectively. CH5424802 acts on NCI-H2228 NSCLC cells expressing EML4-ALK, inhibiting ALK autophosphorylation. CH5424802 can also inhibit STAT3 and AKT, rather than ERK1/2 phosphorylation. CH5424802 completely inhibited Tyr705, a phosphorylation site of STAT3. CH5424802 preferentially acted on NCI-H2228 cells expressing EML4-ALK without acting on negative NSCLC cell lines that contains ALK, including monolayer cultured HCC827 cells (deletion of EGFR exon19), A549 cells (KRAS mutations) or NCI-H522 cells (EGFR wild type, KRAS wild type, and ALK wild type). CH5424802 acted on NCI-H2228 spherocytes, causing apoptosis-caspase-3/7-like activation. CH5424802 cam inhibit the growth of two lymphoma cells, KARPAS-299 and SR, containing NPM-ALK fusion protein and does not affect the growth of HDLM-2 lymphoma cells without ALK fusion. CH5424802 acted on KARPAS-299 with highly targeted selectivity and stronger antiproliferative activity. When CH5424802 inhibits KAPRAS-299, the IC50 is 3 nM. When inhibit KDR, IC50 was 1.4 μM. The metabolic stability of CH5424802 was high.;

• In vivo

  The oral treatment of CH5424802 can inhibit tumor growth. This role is dose-dependent, and the ED50 is 0.46 mg/kg. CH5424802 was treated at a dose of 20 mg/kg, causing a rapid regression of the tumor, with a recurrent rate of 168%. After 11 days of treatment (at day 28), the tumor volume in each mouse was less than 30 mm3, maintaining an effective anti-tumor effect; no tumor regurgitation occurs in no drug treatment period whitin 4 weeks.The half-life and oral bioavailability for CH5424802 treated mice were 8.6 hours and 70.8%, respectively. The mean plasma levels were 1.7, 1.5, and 0.3 nM after the treatment of 6 mg/kg repeated doses for 2, 7, and 24 hours.CH5424802 treatment inhibited tumor growth.Use CH5424802 to treat KARPAS-299 and NB-1 at a dose of 20 mg/kg, and on day 20, tumor growth was inhibited by 119% and 104%.CH5424802 inhibited STAT3 phosphorylation, which is dose-dependent (2-20 mg/kg), a decrease in phosphorylation of AKT was observed in the xenografts treated with CH5424802.;

• ALK Inhibitor

  Rizotinib is a first-generation anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) and plays an important role inthe treatment of ALK-positive advanced non-small cell lung cancer (NSCLC). However, as with other TKIs, resistance development can-not be avoided with crizotinib. Alectinib is a second-generation ALK-TKI developed by Roche, which can effectively solve the problem of crizotinib resistance.

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• Binding Mode

  In the co-crystal structure with human ALK (Fig. 2), alectinib binds to the ATP site with the DFG-in mode, forming one hinge hydrogen bond between the carbonyl oxygen and the backbone NH of Met1199 (vs. two or three hinge hydrogen bonds observed with other ALK inhibitors, such as crizotinib, lorlatanib, brigatinib). This distinct hinge binding likely contributes to its high ALK selectivity. The indole NH hydrogen bonds to amide carbonyl of Gly1269, and the cyano group participates in a complicated network of hydrogen bonds to the neighboring amino acids via the co-crystallized water or ethylene glycol molecules (Fig. 3).
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