March 2024

Arpeggio Pipeline: KEAP1-mutant Lung Cancer

Over the last two decades we have made significant progress on fighting cancer: Today, 99% of patients with prostate cancer and 89% of patients with breast cancer will survive for more than 10 years. Unfortunately, this has not been true for lung cancer where only 17% of patients with lung adenocarcinomas will survive that same period of time. The extremely toxic chemotherapy Cisplatin is often first-line therapy to these patients, however most lung cancers, especially metastasized tumors, often develop resistance quickly.

Recent studies suggest that genetic alterations in the NRF2 pathway cause  resistance to Cisplatin. Patients with an NRF2-activating mutation have a ten-fold worse survival outcome than patients whose tumors lack such a genetic lesion (Figure 1). NRF2 is a transcription factor that can regulate the mRNA expression of hundreds of genes across our genome, many of which control how our cells respond to oxidative stress. Interestingly, many of today’s chemotherapies work to kill tumors via induction of oxidative stress. By mutating KEAP1 (a negative regulator of the NRF2 transcription factor), Lung Cancer develops a big survival advantage when it mutates KEAP1, becoming more resilient to the cytotoxicity brought on by chemotherapy.

Figure 1. Patients with lung cancer are far less likely to survive ten years due to alterations in the NRF2-KEAP1 axis that can confer resistance to first-line chemotherapies such as Cisplatin.

NRF2 biology remains an exciting therapeutic mechanism with a potential to dramatically improve the lives of patients living with Lung Cancer, however transcription factors are notoriously poor pharmacological targets due to their extremely disordered protein nature making traditional medicinal chemistry quite challenging. To identify a small molecule that either directly or indirectly represses NRF2 activity, we turned to our GRETATM technology. GRETATM is an extremely high throughput assay capable of quantitatively measuring the entire transcriptome: the set of more than 20,000 mRNAs and their associated levels. A small subset of these mRNAs are regulated by the NRF2 transcription factor. With this in mind, we can rank compounds by how selective they are at repressing these NRF2 target genes (Figure 2).  

Figure 2. At Arpeggio, we screened a focused and high diversity library of small molecules in H1975 Lung Cancer cell model harboring a KEAP1-mutation for compounds that repress NRF2 target gene expression.

Following identification of a completely novel small molecule that significantly represses NRF2 Transcription Factor activity, we characterized the mechanism of this compound in great detail. This molecule induces markers of oxidative stress by increasing the production of H2O2, kills multiple cancer models that only bear a KEAP1 genetic mutation, and actually leads to the proteasomal degradation of NRF2 itself. Following a few rounds of SAR, we’ve identified an orally bioavailable analog of this hit compound (AR-0184) with an in vivo half-life exceeding 12 hours (Figure 3) that rapidly leads to tumor growth regression in a Human Lung Cancer cell model in vivo.

The emergence of chemotherapy resistance and ultimate lung cancer relapse remains a terrible and deadly outcome for thousands of patients every year. With our novel NRF2 degrader, we hope to give hope and time back to these people living with this devastating disease.

Figure 3. A new NRF2 degrader. A) Cell viability of a lung cancer model (H2122; KEAP1-mutant) as a function of AR4-0184 concentration with an associated EC50 of 84uM. B) A western blot for NRF2 after exposure of AR-0184 at 10uM for 24 hours. C) Mouse in vivo PK curve after oral administration of AR-0184 at 50 mpk.  
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