BH-30643

BH-30643 is an investigational non-covalent, macrocyclic, brain active, mutant-selective OMNI-EGFRTM inhibitor which has demonstrated sub-nanomolar cellular in vitro potency against a broad spectrum of EGFR activating mutations. BH-30643 was designed to overcome the limitations of currently approved EGFR inhibitors, which were discovered over a decade ago without the current, modern understanding of the structure and protein dynamics of mutant EGFRs.

Targeting the disease-driven active conformation—the mutant OMNI effect:
Under normal physiological conditions, wild-type EGFR exists predominantly in an inactive, open conformation with a larger, less-defined ATP-binding pocket. Upon ligand stimulation, wild-type EGFR transitions to the active, closed conformation with a smaller, well-defined ATP-binding pocket to transduce the extracellular signal. The oncogenic activating mutants of EGFR are constitutively active and preferentially adopt the active, closed conformation. Because all oncogenic EGFR mutation types–classical mutations, atypical mutations, exon 20 insertions and acquired resistance mutations—are activating mutations that induce the protein to adopt the active, closed conformation as the mechanism of constitutive signaling, a molecule designed to engage that conformation selectively should achieve both breadth across the mutation space and selectivity over wild-type EGFR in a single, mechanistically integrated way. We believe targeting the active conformation unlocks the potential for OMNI-EGFR activity while maintaining wild-type sparing tolerability.

Eliminating the T790M and C797S vulnerabilities—non-covalent binding: BH-30643 leverages an entirely novel macrocyclic scaffold in an effort to uniquely address both T790M and C797S resistance. Because BH-30643 is not reliant on a back-pocket motif to achieve potency, the T790M mutation—which blocks the binding of first- and second-generation EGFR inhibitors—does not diminish BH-30643’s observed binding affinity. Further, BH-30643’s binding is not driven by covalent attachment and thus, the C797S mutation—which destroys the covalent chemistry by which osimertinib depends—does not reduce BH-30643’s potential therapeutic strength.

Macrocyclic architecture—conformational precision, potency and selectivity: BH-30643 was invented based on a carefully designed macrocyclic architecture, which was chosen based on the unique size of EGFR ATP adenine hinge area to achieve the conformational precision required to distinguish the active mutant conformation from the inactive wild-type conformation with high affinity and selectivity. The use of a macrocyclic scaffold in approved kinase inhibitors—including lorlatinib and repotrectinib, both designed by our scientific founder, Dr. Cui—has demonstrated that this structural approach can achieve exceptional potency, selectivity and pharmacokinetic properties in clinical practice.