Built to break barriers: How Grove Biopharma is archi­tecting its way around traditional drug limits

Macrocycles are most notoriously naturally produced by bacteria, fungi, and marine organisms, which have evolved these molecules as an armament for the inter-microbial warfare that occurs in soils and other envi­ron­ments. Humans have been trying to tweak these natural products to turn them into drugs for decades. There are now more than a dozen FDA-approved macrocyclic peptide drugs, for everything from cancer to kidney disease to candidiasis — they make up about 4 percent of drugs. However, these molecules are difficult to alter to direct them to new targets, as adjusting one feature typically costs the molecule its ability to enter cells, avoid premature degradation, bind the desired target specif­i­cally, or be manufacturable. 

This multi­pa­ra­meter opti­miza­tion problem has been resistant to AI improve­ments (like AlphaFold and derivatives) for a variety of reasons — mostly that the empirical data sets for feature recognition continue to be expensive and hard to produce. Macrocycles are not engi­neer­able today, yet. At DCVC Bio, we’ve consis­tently sought out platforms that can rationally design and efficiently assemble protein-scale ther­a­peu­tics — capable of modulating histor­i­cally intractable intra­cel­lular targets through novel scaffolds, improved cell perme­ability, and tunable phar­ma­co­ki­netics. Our optimism has always been rooted in the evolving convergence of synthetic biology, structural informatics, and molecular engineering.

Enter the bottlebrush: A new therapeutic architecture

When we crossed paths with the team at Grove Biopharma, we saw a solution. Grove is led by scientific founder Dr. Nathan Gianneschi of North­western University, and CEO Dr. Geoffrey Duyk, whose leadership pedigree spans Exelixis and Millennium Phar­ma­ceu­ti­cals. Back in April, we led Grove’s $30 million Series A, and since then, we’ve watched with fascination as they’ve repurposed non-drug-like peptides into viable drug candidates using the elegant chemistry of ring-opening metathesis poly­mer­iza­tion (ROMP). The group is crafting bottle-brush-like polymers that are able to specif­i­cally bind unstruc­tured targets in oncology, inflam­ma­tion, and beyond. 

PLPs or Bionic Biologics are fully synthetic protein mimetics purpose built to target classically intractable intra­cel­lular therapeutic drug targets (e.g. targeting intrin­si­cally disordered regions of proteins or protein-protein inter­ac­tions). They represent protein-scale molecules for protein-scaled solutions. Proteins can be considered precision polymers of amino acids (polyamides), but in contrast PLPs or Bionic Biologics are precision bihybrid branched polymers of peptides (brush bottle polymers) built using living graft through poly­mer­iza­tion of peptides monomers using ROMP. These dynamic macro monomers have a number of emergent properties that overcome the limitations of peptides and macrocyclic peptide chemistry including but not limited to cell perme­ability, pH/protease resistance, avidity driven enhancement of potency, microen­vi­ron­ment-induced predicted secondary/tertiary structure of peptides without requirement for covalent modi­fi­ca­tion, and adaptive binding to targets, including all defined classes of protein-protein interaction surfaces. In addition, PLP chemistry avoids the synthetic and manu­fac­turing complexity of macrocyclic peptides and related chemistry. In contrast to alternative chemistries, PLPs are modular, allowing the uncoupling of opti­miza­tion of potency from phar­ma­cology, and are readily configured into multi­func­tional molecules enabling proximity-induced chemistries, subcellular local­iza­tion, and delivery of payloads. PLPs (20−40 kilodaltons versus 0.5−2 kilodaltons for macro­cyclics) represent protein-scale molecules for protein-scaled solutions.

The resulting molecules are multi­tal­ented. When the peptide bristles are folded up into a ball around the backbone, they’re highly polar and water-soluble, meaning they can travel well in the aqueous envi­ron­ments outside cells. But at the cell wall, the PLPs can unfold, exposing the low-polarity backbone, which allows the molecules to dissolve through the phos­pho­lipid bilayers that makes up all cell membranes. Once inside, the molecules fold up into a ball again for protection from proteolytic degradation. PLPs are program­mable, too, in the sense that the amino acid sequences in each bristle can be tuned to bind to specific proteins inside cells and block processes that can lead to disease. 

One of the first clinical targets Grove is going after is prostate cancer. Cancer cells in the prostate need testos­terone to grow, which is why hormone therapy to block androgen production is a common treatment choice. But even in the absence of androgens, the signaling pathway sparking cell growth can be reactivated if tumor cells happen to acquire a mutant androgen receptor called AR-V7. 

Grove has built, and is currently testing, a PLP that targets and degrades both the wild-type androgen receptor and AR-V7. The advantage of starting with a PLP that degrades AR-V7 is that androgen receptor antagonists are a well understood and validated drug category with a clear unmet need — providing a developed test for Grove’s technology. 

Beyond that, though, Grove is designing PLPs that can disrupt SHOC2, a crucial scaffolding protein involved in the RAS/RAF/MAPK signaling pathway that controls cell division and differ­en­ti­a­tion, including in cancer. Several other targets round out their aspirations to create the first PLP drug modality platform.

PLPs will provide a totally new modality for treating cancer and other common health problems — one that will compete with and (thanks to PLP’s manu­fac­tura­bility) likely surpass macrocyclic peptides to become the antibody for inside cells. We think the Grove team is brilliantly qualified to pursue this vision, and we’re excited to follow their progress toward clinical trials.