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KDDF-201208-07 Optimization of reversible small molecule inhibitors for EGFR T790M(Oncology, Chemical) [01.04.2013]


Development and Market Objectives

  • Our objective is to develop an effective anti-cancer drug for Non-small cell lung cancers (NSCLC) that express the EGFR T790M mutation, with resistance to tyrosine kinase inhibitors.

    We aim to develop a preclinical candidate substance and reversible small molecule inhibitor with specificity for EGFR T790M.

Figure 1. EGFR signal transduction pathways. With the binding of ligands such as EGF, the EGFR family receptors form homo- and heterodimers for full activation (Lung Cancer, 2012, 131).

Unmet Medical Need & Target Patients

- Target Patient Population:

○   EGFR is a receptor tyrosine kinase involved in cell survival and proliferation. The overexpression of EGFR and activating mutations are associated with the occurrence of several cancers. One prominent example is non-small cell lung cancer (NSCLC).

○   EGFR overexpression can be identified in approximately 40-80% of patients with non-small cell lung cancer and is closely associated with a very poor prognosis. Approximately 90% of patients exhibiting abnormal expression of EGFR harbor a deletion of Exon 19 or the L858R mutation. Of these, NSCLCs with acquired resistance to first-line EGFR TKIs expressing the EGFR T790M mutation constitute our target patient population.

○   Gefitinib (Iressa) and erlotinib (Tarceva) are Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) with high initial efficacy as anti-cancer drugs. However, the emergence of resistance remains a major problem and no available treatment exists for resistant cancers arising from the T790M mutation.


Figure 2 - Frequency of resistance mechanisms against EGFR TKIs (Clinical Cancer Research, 2011, 5530).

○    Resistance occurs within an average of 6-14 months after administration of EGFR-TKIs to patients with NSCLC. Approximately 60% of resistance arises through the T790M point mutation and no treatment options exist for this condition.

○    Recent studies on pan-HER inhibitors and irreversible EGFR T790M inhibitors have been conducted. However these candidates inhibit the wild-type form of the receptor, leading to significant cytotoxicity. 

○    Therefore, a selective inhibitor for the EGFR T790M (EGFR Mutant-Selective Inhibitor, EMSI) is urgently needed to suppress first & second-line NSCLCs. The development of irreversible inhibitors has the advantages of lower development costs and increased development speed. 


○   We will ensure mutant selectivity for our TKI candidates (via in vitro kinase assays) and select compounds that exhibit a binding affinity for T790M that is at least 500 times higher than existing drugs.

○   By analysing changes in IC50 dependent upon ATP concentrations, candidates that are reversible inhibitors can be identified and excluded.

○   Candidates that exhibit inhibitory effects against cell proliferation in the H1975 line with T790M mutation will be selected for further studies in other cell lines.


Intellectual Property

○   Among our candidate compounds, some were registered for patents, with additional patents to be applied for based on future research results.


Competitive Advantages

○   The existing irreversible panHER inhibitor effectively inhibits T790M, but shows little efficacy in clinical settings. If the dosages are increased for effective treatment, side effects (including rash and diarrhea) are very serious, due to the irreversible inhibition of wild-type EGFR.

○   Currently, two candidates that are T790M selective and irreversible inhibitors are being prepared for clinical Phase 1, but some difficulties in development are expected due to concerns with unpredictable side effects and the absence of PK parameters.

○   Our candidate is highly selective to T790M and importantly, exhibits extremely low affinity for EGFR wild-type. Therefore, less concern exists regarding dose-limiting toxicity which is a major issue for EGFR-TKIs.

○   In addition, as opposed to reversible inhibitors, there is relatively less concern about the expected drawbacks of irreversible inhibitors. This enhances the competitiveness of our candidate



non-small cell lung cancer (NSCLC)

Research Period

Nov. 1, 2012~May. 31, 2015


Chung-ang university

Developmental Stage

drug candidate

Additional Information

Contact Information

Address Company Name: Chung-Ang University, Pharmaceutical College
WebSite Homepage: Contact Person: Kyung Hun Min
E-mail: Contact: +82-2-820-5599

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