Characterization of HER2 inhibitors with a novel mechanism of action

ABSTRACT
About 1 in 8 women in the U.S. will develop invasive breast cancer during their lifetime. Human
Epidermal growth factor Receptor-2 (HER2) is a clinically validated target that is upregulated in 25% of
these cancers and is associated with poor disease prognosis. Current medications targeting HERs have
several limitations because of their inadequate effectiveness and sensitivity to resistance by cancer cell
mutations, causing treatment failure. HER receptor family requires an important dimerization step for
activation that is essential for cancer cells to maintain growth and division. Inhibition of dimerization is
currently clinically achieved with antibodies that cannot target mutated truncated receptor forms and
cannot cross the blood-brain barrier, turning the brain into a sanctuary for cancer cells and leading to
metastasis and relapse.
Our lab discovered a small molecule through virtual screening; molecular modeling algorithms
predict it will bind to the HER2 dimer interface surface, which would allosterically inhibit the receptor
activation by preventing dimerization. This molecule was shown in cellular assays to inhibit SKBr3 cancer
cell lines overexpressing HER2 in a selective and non-toxic manner. This is the first-in-class molecule to
target a member of this receptor family using an allosteric inhibition mechanism. If advanced for clinical
testing, it can work as a stand-alone therapy for patient populations that resist current medications or in
combination therapies to decrease resistance, metastasis, and relapse. The overall objective of this
proposal is to characterize and validate analogs of this inhibitor predicted by modeling to share a similar
binding pose and the same or higher affinity to the HER2 dimer interface. We will validate their
interaction with HER2 using cellular, biophysical, and biochemical assays. We will also study their effect
on cancer cells' downstream targets expression and phosphorylation levels and test the top-performing
lead compound plasma distribution properties and efficacy in HER2+ breast cancer in vivo models.
The proposed study is innovative due to the new mechanism of inhibition proposed by modeling
and indicated by the selective toxicity shown in cellular studies. Our long-term goal is to extend this
research to related receptors in the same family (EGFR, HER3, and HER4) that are implicated in many
solid tumors, some of which lack targeted therapies. The outcomes of this study will offer proof of
concept to usher in a new class of anticancer agents targeting HER2 receptors. The project will support
research experiences in cancer drug discovery and therapeutics to six PharmD, one graduate, and six
undergraduate students in two REAP-eligible institutions.

Grant Number: 1R15CA283780-01A1
NIH Institute/Center: NIH
Principal Investigator: May Abdelaziz