Nondegradative Synthetic Molecular Glues Enter the Clinic

Abstract

Molecular glues are small molecules that can induce or stabilize protein-protein interactions between proteins inside cells. Unlike classical small molecule drugs, molecular glues can target challenging disease-causing proteins lacking well-defined binding pockets. Nature has repeatedly used this mode of action, but identifying molecular glues for new target proteins has been a major challenge. Recently, manmade molecular glues, inspired by natural products, for KRas, entered clinical trials although KRas is a major cancer target long thought to be undruggable. Here, how these molecules are initially discovered and optimized to provide several advanced drug candidates for various KRas-dependent cancer types are outlined. The major insights obtained for this new class of drug modalities are further summarized. These results showcase how molecular glues that do not rely on protein degradation can provide clinical benefits for challenging drug targets.

Keywords: KRas; covalent warheads; cyclophilin; macrocycles; molecular glues.

Figure 1

Development of RMC‐6291. A) Natural product immunophilin binders (sanglifehrin A, FK506, and cyclosporin A), where CypA/FKBP‐binding parts are highlighted in purple. B) Synthetic analogs derived from the natural products shown in (A), which contain a covalent warhead; for probe‐1, the primary CypA and KRas‐binding parts are shadowed yellow and cyan, respectively. C) The sanglifehrin A‐based covalent probe (probe‐1) was further optimized through macrocyclization of the initial macrocyclic core (core‐1), which was the basis for all advanced macrocyclic KRas^G12C inhibitors (core‐2). The parts of the molecules that were added for the ring closure of the macrocycle are highlighted in red, and parts kept the same as in sanglifehrin A are shown in purple. D) KRas^G12C‐targeting compounds cmpd‐1, RM‐018, RMC‐4998 (shadowed based on CypA/KRasG12C interactions as for probe‐1), and RMC‐6291^{[ 42 ]} were derived from core‐2 by elaboration of the linker part (marked in blue) connecting macrocycle core (core‐2) to the warhead. E,F) Ternary complexes of cyclophilin A (yellow surface), KRas^G12C (cyan surface with amino acids in cyan lines for better visibility), and probe‐1 (E) green sticks, covalently bound to KRas^G12C, PDB‐ID 8g9q) or RMC‐4998 (F) magenta sticks, bound to KRasG12C, PDB‐ID 8g9p). G) Table with binding and inactivation constants for the shown inhibitors.

Figure 2

A) Ligand development of the pan‐Ras inhibitors RMC‐7977 and RMC‐6236 together with assay results. The primary CypA and KRas‐binding parts are shadowed yellow and cyan, respectively.^{[ 51} , ⁵² , ^{73 ]} B) Alignment of the ternary complexes between CypA, RMC‐7977 and the respective targets H‐Ras (PDB:8tbg), K‐Ras (PDB:8tbf), and N‐Ras (PDB:8tbi) with CypA colored in yellow, the Ras proteins colored in green, and the switch regions colored in red.^{[ 51 ]} C) Structure of the KRas^G12D‐reactive molecular glue RMC‐9805.^{[ 42} , ^{57 ]} Similarities to previous compounds are colored red and green, and new elements are highlighted in blue. D) Scaffold for emerging bridged macrocyclic ligands from recent patents that are inspired by the KRas‐targeting molecular glues from Revolution Medicines.^{[ 58 ]} E) A patent evading structure similar to the RMC compounds published in a patent by Hansoh Pharma.^{[ 59 ]} F) A patent‐evading structure similar to RMC‐6236 published in a patent application by Roche.^{[ 68 ]} G) A patent‐evading structure similar to the RMC compounds for the use in an antibody‐drug conjugate, published in a patent application by Novartis.^{[ 60 ]}