Circle Pharma

Somewhere in a lab off Gateway Boulevard, a pill is doing something a pill should not be able to do.

Right now, in a clinic, a patient with an advanced solid tumor is swallowing a molecule called CID-078. It is a macrocycle - a ring-shaped compound roughly the size of a problem that medicinal chemists spent two decades calling unsolvable. It is supposed to slip inside a cell, find a protein called a cyclin, and interrupt the machinery that lets cancer keep dividing. And it is supposed to do all of this after being taken by mouth, which is the part that makes the rest of the field raise an eyebrow.

Circle Pharma is the company that put that pill there. It is small - roughly 67 people - and it is not yet selling anything. What it has instead is a thesis, a platform with the slightly intimidating name MXMO, and more than $200 million in venture funding from investors who decided the thesis was worth the wait.

Most of the proteins that drive disease are too flat, too slippery, or too sociable to drug.

Here is the inconvenient truth of drug discovery. Small-molecule pills are wonderful at jamming into deep, well-defined pockets - the kind enzymes politely provide. But a huge share of disease biology runs on protein-protein interactions: broad, shallow surfaces where two proteins shake hands. There is no pocket to jam. Small molecules fall off. So the industry quietly labeled those targets "undruggable" and moved on, which is a tidy way of saying it gave up.

Biologics - antibodies and the like - can grip those surfaces, but they are large, expensive, and famously bad at getting inside cells or being taken as a pill. That leaves a gap in the middle of the molecular world. Cyclins, the master regulators that tell a cell when to divide and that many cancers hijack, sit squarely in that gap.

Two professors looked at the gap and saw a sweet spot instead.

Circle Pharma was founded in 2012 by Matthew P. Jacobson, a computational chemist from UC San Francisco, and R. Scott Lokey, a peptide chemist from UC Santa Cruz. Jacobson had already helped start Global Blood Therapeutics and Relay Therapeutics, so he had a track record of betting on hard chemistry and being right. Lokey had spent years studying the one property that made macrocycles so frustrating: cell permeability.

Their bet was specific. Macrocycles are big enough to wrap around a flat protein surface the way a small molecule never could, yet - if designed with enough care - small and tuned enough to cross a cell membrane and even survive a trip through the gut. The catch is that "designed with enough care" is doing an enormous amount of work in that sentence. Predicting whether a given ring will be cell-permeable is brutally hard. That prediction problem is exactly what Lokey had spent his academic career on.

The University of California's QB3 incubator and Mission Bay Capital backed the launch, and in a moment the company itself later called "full circle," Pfizer signed on early - first as a seed investor, then in a deal to build a screening library of macrocyclic peptides.

MXMO is the part where guessing turns into engineering.

The MXMO platform is Circle Pharma's answer to the permeability problem. It stitches together four things that usually live in different buildings: structure-based rational drug design, artificial intelligence and machine learning, physics-based simulation, and advanced synthetic chemistry. The point is to design a macrocycle on a screen, predict whether it will actually get into a cell, and then make it - then close the loop and do it again, faster each time.

A thesis is cheap. A patient in a Phase 1 trial is not.

The clearest evidence that the bet is more than a slide deck is that CID-078 exists, cleared an IND, and is in humans. Getting a designed macrocycle from a screen to a first-in-class oral oncology candidate is the kind of thing that does not happen by accident. The money agrees: investors have put more than $200 million into the company across rounds, including a $90 million Series D in 2024.

Partnerships round out the picture. Pfizer was there early, both as a seed backer and through a macrocyclic-peptide library agreement. Eli Lilly joined the Series C. These are not the kinds of names that attach themselves to a hunch.

The goal is bigger than one drug, and it is named in the tagline.

"Drugging the undruggable" sounds like marketing until you remember that the undruggable proteome is most of the proteome. Circle Pharma's stated mission is to harness macrocycles to transform the treatment of cancer, starting with cyclins. But the real prize, if the platform holds, is a repeatable way to reach targets that small molecules and biologics both miss. CID-078 is the first test of whether the method generalizes. The cyclin D1 program is the second.

Back to that pill.

Return to the patient off Gateway Boulevard, swallowing CID-078. A decade ago, the target it is aiming at was on the industry's "do not bother" list. The molecule itself - an oral macrocycle tuned to cross a membrane and grip a flat protein surface - would have been treated as a chemistry party trick rather than a therapy. Now it is in a clinical trial, with a platform behind it and real money betting it is the first of many.

Nothing is proven yet. Phase 1 is early, biology is unsentimental, and most drug candidates do not make it. Circle Pharma has not changed cancer treatment; it has earned the right to try. But the scene in that clinic is already different from the one the field assumed was permanent. The undruggable list got one entry shorter. The interesting question is how much shorter it gets.