Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY Small molecule EGFR inhibitors constitute the recommended therapy for EGFR-positive non-small cell lung cancer (NSCLC). Resistance was first reported to EGFR inhibitors through mutations in the ATP pocket that was addressed by a new generation of irreversible EGFR inhibitors. However, resistance has continued to evolve with the more recent contributors of resistance being the L858R/T790M/C797S mutations in mEGFR+ NSCLC and mutant KRAS signaling that bypasses EGFR inhibition in mKRAS+ NSCLC. There are currently no viable EGFR-mediated treatments for mKRAS+ NSCLC. Our goal is to develop novel molecules that provide more effective options to treat mKRAS+ and mEGFR+ NSCLC. Aurora kinases (AURK) are mitotic kinases involved in centrosome maturation and separation during mitosis. In addition, aurora kinases drive tumorigenesis and metastasis. Aurora kinase inhibitors have demonstrated improved anticancer effects when used in combination with EGFR inhibitors in both mKRAS+ and mEGFR+ NSCLC. Thus, dual EGFR/AURK inhibition provides a unique approach to overcome resistance to EGFR inhibitors. We have identified novel molecules with dual EGFR/AURK inhibition in our lab. Our compounds demonstrated nanomolar to micromolar potencies against EGFR and AURK. Additionally, our compounds demonstrated preferential inhibition of EGFR and AURK in a 96- kinase selectivity panel. The goal of this proposal is to optimize lead molecules identified in our lab for potent dual EGFR and AURK inhibition that would translate to enhanced antiproliferative effects in mKRAS+ and mEGFR+ NSCLC. In Aim 1, we will synthesize novel series of compounds as analogs of our lead compounds. We will evaluate the compounds in enzymatic assays against EGFR, mutant EGFR and aurora kinases. Solubility will also be assessed. In Aim 2, we will evaluate potent dual EGFR/AURK inhibitors identified from Aim 1 for anticancer effects in mKRAS+ and mEGFR+ NSCLC and toxic effects in normal lung cells. In Aim 3, we will investigate selectivity for dual EGFR/AURK inhibition versus off-target kinases and metabolic stability for potent dual EGFR/AURK inhibitors identified from Aim 2.
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