# Developing novel LOX inhibitors to target chemotherapy resistant TNBC

> **NIH NIH R42** · LOXIGEN, INC. · 2024 · $992,932

## Abstract

PROJECT SUMMARY
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It accounts for ~15% of
all breast cancer yet is responsible for 30% of breast cancer deaths. TNBC is treated primarily by conventional
chemotherapy; however, resistance to therapy is common, leading to high mortality rates. Importantly, the
benefit of current therapeutic strategies used in chemoresistant TNBC; i.e., immunotherapy and antibody-
drug conjugates, is confined to only a fraction of patients, and survival benefit is limited. Therefore, there is
an urgent need to identify novel and effective treatment strategies to overcome resistance to chemotherapy.
Recently, we identified hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key mediator of
chemoresistance in TNBC (Saatci et al, Nature Communications, 2020). We showed that LOX is
overexpressed in chemoresistant tumors, and its inhibition re-sensitizes the most aggressive breast tumors
to doxorubicin using several clinically-relevant mouse models. However, the available LOX inhibitors are
either non-selective or has toxicity. Hence, our main objective in this project is to develop potent, specific and
well-tolerated LOX inhibitors to overcome chemoresistance in TNBC that has a high translational potential.
Through high-throughput compound library screening and hit-to-lead conversion studies, we identified
compounds with potent on-target cellular engagement of LOX, with good oral pharmacokinetics (PK) and
with chemosensitizer effect without major toxicity (US PTO 17/693,371 and PCT/US2022/20086, patent
pending). Starting from our current non-optimized lead molecule, we aim to develop lead compounds with
increased potency, safety and drug-likeness. To accomplish this goal, in Phase I of this Fast-Track STTR
grant, we will generate a diverse library of small molecules via an extensive structure activity relationship
(SAR) study using our initial pharmacophore. We will test the synthesized inhibitors with respect to the degree
of LOX enzymatic activity inhibition, LOX binding and selectivity towards LOX. We will perform the off-target
assessment of the inhibitors using CEREP screen as well as kinome profiling. The shortlisted candidates will
further be tested in ECM crosslinking and 3D chemosensitization assays using both cell lines and organoids.
Inhibitors with better efficacy, selectivity and stability will move to Phase II. In Phase II, we will perform several
ADME assays, including metabolic stability/identity, Caco-2 permeability and transport, cardiotoxicity and
genotoxicity, plasma protein binding, CYP inhibition/induction/reaction phenotyping to improve drug-like
properties while maintaining on-target potency in TNBC cells. Detailed PK/PD and toxicity analyses of the
most promising candidates will be carried out followed by testing their chemosensitizer effect using both
state-of-the-art immunodeficient (cell line- and patient-derived xenografts) and immunocompetent
(syngeneic) ...

## Key facts

- **NIH application ID:** 11116003
- **Project number:** 4R42CA275622-02
- **Recipient organization:** LOXIGEN, INC.
- **Principal Investigator:** Ozgur Sahin
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $992,932
- **Award type:** 4N
- **Project period:** 2023-06-08 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11116003

## Citation

> US National Institutes of Health, RePORTER application 11116003, Developing novel LOX inhibitors to target chemotherapy resistant TNBC (4R42CA275622-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11116003. Licensed CC0.

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