HKI-357 is a potent, dual irreversible inhibitor of ErbB2 (HER2) and EGFR. HKI-357 suppresses ligand-induced EGFR autophosphorylation and cell proliferation in NCI-H1975 cells containing L858R and T790M mutations.

CUDC-101 is a multi-targeted agent designed to inhibit epidermal growth factor receptor (EGFR), human epidermal growth factor receptor Type 2 (Her2) and histone deacetylase (HDAC). This drug synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. Thus, a single compound may offer greater therapeutic benefits, which is verified in clinical trial phase I for the treatment patients with advanced head and neck, gastric, breast, liver, and non-small cell lung cancer tumors. In April 2013, CURIS, INC determined that they would discontinue enrolling patients in phase 1 expansion trial of the intravenous formulation of CUDC-101, and that the future development of CUDC-101 would be dependent on our ability to successfully develop an oral formulation of CUDC-101. However, the efforts to develop an effective oral formulation with improved bioavailability have not resulted in significant improvements when compared to the intravenous formulation of CUDC-101. As a result, at this time CURIS no longer plan to make material investments in this program.

MP-412 (AV-412) is a potent dual inhibitor of EGFR and ErbB2 tyrosine kinases, including the mutant EGFR (L858R,T790M), which is clinically resistant to the EGFR-specific kinase inhibitors erlotinib and gefitinib. AV-412 has potential as a therapeutic agent for the treatment of cancers expressing EGFR and ErbB2, especially those resistant to the first generation of small-molecule inhibitors.AVEO Pharmaceuticals was developing AV-412 for the treatment of cancer, however development has been discontinued.

Sapitinib is an oral, reversible and equipotent inhibitor of EGFR, HER2 and HER3 signalling. The drug was tested in phase II of clinical trials in patients with breast cancer, colorectal cancer, gastric cancer and NSCL carcinoma, however its development for breast cancer therapy seems to be terminated. Sapitinib absorption is rapid and the drug is totally cleared by metabolism with the major routes being oxidation and amine or ether cleavage around the piperidine ring with subsequent glucuronide or sulphate conjugation.

TAK-285 is a novel low-molecular weight compound that was designed, synthesized by Takeda Pharmaceutical Company, Osaka, Japan, and has been shown to selectively and potently inhibit HER2 and EGFR kinase activities. Biochemically, TAK-285 inhibits HER2 and EGFR phosphorylation, with 50% inhibition concentrations of 17 and 23 nmol –1, respectively. This drug was in the phase I of clinical trial for the treatment of solid rumors and cancer but was discontinued due to strategic reasons. In addition was investigated that TAK-285 is not Pgp substrates, which is why it may be useful in the development of agents with the potential to treat brain metastases.

AEE-788 is an orally available anticancer agent that was being developed by Novartis. AEE-788 is a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. At the enzyme level, AEE-788 inhibited EGFR and VEGF receptor tyrosine kinases in the nm range (IC(50)s: EGFR 2 nm, ErbB2 6 nm, KDR 77 nm, and Flt-1 59 nm). In cells, growth factor-induced EGFR and ErbB2 phosphorylation was also efficiently inhibited (IC(50)s: 11 and 220 nm, respectively). AEE-788 demonstrated antiproliferative activity against a range of EGFR and ErbB2-overexpressing cell lines (including EGFRvIII-dependent lines) and inhibited the proliferation of epidermal growth factor- and VEGF-stimulated human umbilical vein endothelial cells. These properties, combined with a favorable pharmacokinetic profile, were associated with a potent antitumor activity in a number of animal models of cancer, including tumors that overexpress EGFR and or ErbB2. Oral administration of AEE-788 to tumor-bearing mice resulted in high and persistent compound levels in tumor tissue. Moreover, AEE-788 efficiently inhibited growth factor-induced EGFR and ErbB2 phosphorylation in tumors for >72 h, a phenomenon correlating with the antitumor efficacy of intermittent treatment schedules. AEE-788 has potential as an anticancer agent targeting deregulated tumor cell proliferation as well as angiogenic parameters. AEE-788 had been in phase Ⅱ clinical trials by Novartis for the treatment of glioblastoma multiforme. However, this research has been discontinued.

Varlitinib (Alternative Names: ARRY-334543; ARRY-543; ASLAN-001; Varlitinib tosylate) is a small molecule based reversible pan-HER inhibitor of EGFR, HER2 and HER4. In response to the binding of various ligands, these kinases undergo heterodimerisation and homodimerization, resulting in activation of numerous growth factor signaling pathways, by inhibiting the activation of the HER receptors via drug, effects such as shrinkage of the tumor and longer survival can be anticipated. In a large variety of cancers, the overexpression and/or constitutive activation of EGFR and HER2 are often observed and frequently correlate with poor clinical prognosis. Licensed from Array BioPharma with global rights for all indications, varlitinib is being developed as first-in-class drug for cholangiocarcinoma, gastric and colorectal cancer, and as best-in-class drug for breast cancer.

Pelitinib (EKB-569) is a 3-cyanoquinoline pan-ErbB tyrosine kinase inhibitor with potential antineoplastic activity. Pelitinib irreversibly binds covalently to epidermal growth factor receptors, thereby inhibiting receptor phosphorylation and signal transduction and resulting in apoptosis and suppression of proliferation in tumor cells that overexpress these receptors. Pelitinib had been in phase II clinical trials for the treatment of non-small cell lung cancer and colorectal cancer. Treatment-emergent adverse events were diarrhea, abdominal pain, gastrointestinal carcinoma, intestinal obstruction and vomiting.

BMS 599626 is a selective and efficacious inhibitor of HER1 and HER2 with IC50 of 20 nM and 30 nM. BMS-599626 is identified as an ATP-competitive inhibitor for HER1 and as an ATP-noncompetitive inhibitor for HER2. BMS-599626 inhibits the proliferation of tumor cells expressing high levels of HER1 and/or HER2, including Sal2, BT474, N87, KPL-4, HCC202, HCC1954, HCC1419, AU565, ZR-75-30, MDA-MB-175, GEO, and PC9 cells. In a phase I trial of solid tumour patients receiving BMS 599626 no doselimiting toxicities were observed during the first cycle. Grade 1 or 2 drugrelated effects were reported and included diarrhoea, nausea, vomiting, rash, fatigue, musculoskeletal pain/cramp and cough. BristolMyers Squibb discontinued development of BMS 599626 for cancer in July 2015