Thursday, April 9, 2015

Drugs in Clinical Pipeline: Allitinib

Allitinib [N-[4-[[3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl]amino]quinazolin-6-yl]acrylamide] is an orally active, highly selective irreversible inhibitor of the erbB family receptor tyrosine kinases (HER1, HER2, and HER4) [1]. In preclinical trials, the IC50 values of Allitinib inhibiting EGFR and HER2 were 0.5 and 3 nM, respectively, which were 5-15-fold more potent than Afatinib and Dacomitinib. Allitinib could potently inhibit the EGFR T790M mutant, exhibiting an IC50 value of 12 ± 2 nM, which is similar to Afatinib (IC50 = 10 nM) and approximately 500-fold more potent than Lapatinib [1]. In human tumor xenograft models that expressed or overexpressed HER family members, Allitinib showed antitumor activities, especially against those with HER2 overexpression or EGFR T790M mutant tumors [1].

Allitinib an analogue of Lapatinib, is currently in clinical trials in China for the treatment of solid tumors. Pilot studies in our laboratory demonstrated that Allitinib was absorbed quickly, reaching Cmax in 1.8-3.0 h. The mean half-life of Allitinib was estimated to be approximately 4 h. The concentration of Allitinib in plasma was low because of the poor solubility and permeability and extensive first-pass metabolism. High inter-patient variability was observed after oral dosing Allitinib tosylate tablets. An α, β-unsaturated carbonyl group was introduced to the structure of Allitinib, which was proved to be the key chemical group for the irreversible inhibition of EGFR and ErbB2. In vitro studies have demonstrated that the efficacy of Allitinib is superior to that of Lapatinib [2].

Common Name: Allitinib
Synonyms: AST-1306; AST1306; AST 1306; ALS1306
IUPAC Name: N-[4-[[3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl]amino]quinazolin-6-yl] acrylamide
CAS Number: 897383-62-9
Mechanism of Action: Kinase Inhibitior; EGFR Inhibitor; ERBB2 Inhibitor; ERBB3 Inhibitor
Indication: Various Cancers
Development Stage: Phase I (China)
Company: Allist Pharmaceuticals

Eidogen Sertanty Inc Provides Kinase Knowledge Base (KKB): a Collection of nearly 1.6 M Kinase Inhibitors.

Importantly, Allitinib functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that Allitinib inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to Allitinib, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to Allitinib antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to Allitinib. In vivoAllitinib potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu) transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of Allitinib in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (=24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish Allitinib as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells [1].

Phase I Study

A phase I, open-label, dose-escalation study to evaluate the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor effects of oral AST1306 is reported [3]. In addition the effects of food on PK was tested.


A modified Fibonacci 3 plus 3 dose-escalation design was employed to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) in patients with advanced solid tumors. The following dose levels were investigated: once daily (QD) at two dose levels (400-and 800 mg), twice daily (BID) in five dose levels (600-, 800-, 1000-, 1200- and 1500 mg), and three times daily (TID) in three dose levels (800-, 1000- and 1200 mg). In the PK and extension study, at least eight patients per dose cohort in three dose levels (maximum tolerated dose [MTD], one or two doses level lower than the MTD) were enrolled to evaluate the PK profiles.


Seventy-one patients were enrolled, with breast (n = 22) and lung cancers (n = 14) being the most common primary cancers. The most frequent drug-related adverse events were grade 1 to 3 diarrhea and rash, grade 1 to 2 fatigue. During dose escalation, the key DLT was grade 3 diarrhea observed in 5 patients at 1000 mg BID (n = 1), 1500 mg BID (n = 1), 800 mg TID (n = 1) and 1200 mg TID (n = 2). AST1306 was rapidly absorbed and had moderate to high clearance. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Under fed conditions, the mean Tmax was prolonged, Cmax was increased, and AUC0-8 was raised. Of the 55 evaluable patients, 7 patients experienced partial responses, including 5 with breast cancer, 1 with lung cancer, and 1 with gastric cancer. The best response with stable disease for = 6 months was achieved in 7 patients.


Based on the DLT and PK profile, the RP2D was defined as 1000 mg TID with evidence of preliminary anti-tumor activity. Further studies are recommended.


1. Xie, H.; et. al. AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo. PLoS One 2011, 6(7), e21487.
2. Lin, L.; et. al. Development and validation of a sensitive LC-MS/MS assay for the simultaneous quantification of allitinib and its two metabolites in human plasma. J Pharm Biomed Anal 2013, 86, 49-55.
3. Cao, J.; et. al. A phase I study of AST1306, a novel irreversible EGFR and HER2 kinase inhibitor, in patients with advanced solid tumors. J Hematol Oncol 2014, 7, 22.