Bionic Biologics are opening new frontiers in drug discovery

The emergence of Androgen Receptor variants, including splice variants such as AR-V7, appear to be important determinants for the emergence of resistance to current therapies observed in castrate-resistant prostate cancer (CRPC). In a groundbreaking approach, Grove has pioneered innovative molecules that simultaneously target and degrade both the Androgen Receptor (AR) and its resistant counterpart, AR-V7. This dual-action strategy not only tackles the primary oncogenic driver but also disrupts the underlying resistance mechanism, offering a powerful and unified solution in the fight against prostate cancer.

The RAS-RAF pathway stands out as one of the most frequently altered pathways in human cancers, playing a critical role in tumor progression. At the heart of this network lies SHOC2, a crucial scaffolding protein that orchestrates the assembly of key players like MRAS and the phosphatase PP1C, forming a dynamic complex that activates the RAS-MAPK signaling cascade.

Leveraging the cutting-edge Grove platform, we have successfully engineered proprietary molecules that can disrupt SHOC2—an endeavor once deemed impossible due to its classification as an "undruggable" target. The Grove SHOC2 disruptor represents a novel approach to combat a wide array of cancers driven by RAS mutations, including non-small cell lung, colorectal, and pancreatic cancers. Moreover, this innovative therapy holds the potential to be used in combination with MEK inhibitors, paving the way for more effective and targeted cancer treatment strategies.

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Myc, a well-established oncogenic transcription factor, is a master regulator of cell growth and proliferation, known for its intricate network of interactions with various partners. The Myc/WDR5 complex facilitates recruitment to chromatin where each protein can activate genes responsible for uncontrolled cell growth and proliferation of cancer stem cells.  Both Myc and WDR5 have been implicated as key oncogenic drivers across a spectrum of malignancies, including glioblastoma (GBM), pancreatic, breast, prostate, gastric, colorectal, bladder cancers, as well as mixed-lineage leukemias, lymphomas, and neuroblastoma.  Grove has crafted compounds that specifically target the Myc/WDR5 interaction, leading to the degradation of WDR5. This innovative strategy opens up exciting therapeutic avenues for treating tumors that are dependent on Myc/WDR5, offering hope for more effective interventions in cancers that have long posed significant treatment challenges.

Myc is one of the most thoroughly studied oncoproteins, whose activity is finely tuned by interactions with various chaperone proteins. Myc contains an N-terminal transactivation domain (TAD) that initiates specific oncogenic transcription programs when paired with key binding partners, like c-Myc/PNUTS/PP1 and n-Myc/AurA.

C-Myc relies on its chromatin cofactor PNUTS to recruit the PP1 phosphatase, which is essential for Myc's stability and chromatin binding. Disrupting PP1 causes c-Myc to become hyperphosphorylated and targeted for proteosomal degradation.

N-Myc’s interaction with Aurora-A kinase plays a pivotal role in cancers like neuroblastoma, where MYCN amplification is a critical poor prognostic factor. N-Myc also is implicated in medulloblastoma, certain AML subsets, and neuroendocrine prostate cancer (NEPC). Aurora-A stabilizes N-Myc, but breaking this connection can trigger N-Myc degradation and tumor regression in animal models.

In response, Grove has developed a cutting-edge TAD-targeted molecule that specifically disrupts these protein interactions, leading to the degradation of both c-Myc and N-Myc. The Grove MYC/TAD disrupter offers a novel strategy to combat cancers driven by these powerful oncoproteins.

Tau is a microtubule-associated protein that stabilizes neuronal cytoskeletal structure, but in Alzheimer’s disease (AD), it becomes hyperphosphorylated and forms neurofibrillary tangles, contributing to neurodegeneration. As a drug target, tau offers a therapeutic strategy beyond amyloid-beta, particularly in later stages of AD where tau pathology correlates more strongly with cognitive decline. Targeting tau formation and inducing degradation may help halt or reverse neurodegenerative processes and improve clinical outcomes in AD patients.

Previous tau-targeted treatments have primarily focused on broad tau clearance, aggregation inhibition, or microtubule stabilization, often lacking isoform specificity and precision. In contrast, the Grove approach targets the 4R tau isoform’s unique structural motif, offering a tailored therapeutic intervention for tauopathies, such as AD, Corticobasal Dementia (CBD), and Progressive Supranuclear Palsy (PSP) (Longhini et al., bioRxiv, 2025).

The Keap1-Nrf2 pathway is a key defense against oxidative and electrophilic stress. Keap1 normally represses Nrf2, promoting its degradation, but under stress, Nrf2 escapes and activates genes that protect cells. Nrf2 activation may play a role in shielding against chronic lung and liver diseases, autoimmune and neurodegenerative disorders, and certain metabolic conditions.

Selective inhibition of the Keap1-Nrf2 protein interaction can boost the antioxidant response, offering therapeutic potential for neurodegenerative diseases. Grove’s proprietary PLPs target Keap1, displacing Nrf2, which then activates the antioxidant response element (ARE) in neuronal cultures (Carrow et al., Advanced Materials, 2024). These Keap1/Nrf2-inhibitory PLPs thus hold promise for treating diseases linked to oxidative stress dysregulation, such as neurodegeneration.