Discovery of 1H-Pyrazole Biaryl Sulfonamides as Novel G2019S-LRRK2 Kinase Inhibitors

Abstract

G2019S (GS) is the most prevalent mutation in the leucine rich repeat protein kinase 2 gene (LRRK2), a genetic predisposition that is common for Parkinson's disease, as well as for some forms of cancer, and is a shared risk allele for Crohn's disease. GS-LRRK2 has a hyperactive kinase, and although numerous drug discovery programs have targeted LRRK2 kinase, few have reached clinical development. We report the discovery and preliminary development of an entirely novel structural class of potent and selective GS-LRRK2 kinase inhibitors: biaryl-1Hpyrazoles.

Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2

“…We note that that the carbonyl oxygen on the five-membered ring of Inhibitor 1 acts as a hydrogen-bond receptor with respect to the backbone amidic nitrogen of Ala1950. This is consistent with the previous computational finding that the formation of a hydrogen bond with the backbone group of Ala1950 would be necessary for an LRRK2 inhibitor to be bound tightly in the ATP-binding site [ 13 , 14 , 15 ]. The phenolic oxygen of Inhibitor 1 also receives a hydrogen bond from the sidechain of Arg1957 at the bottom of hinge region.…”

“…As shown in Figure 3 , a total of 5000 molecules were selected as initial virtual hits in the binding free energy calculation. Keeping in mind that the formation of a hydrogen bond in the hinge region is a common feature of the potent LRRK2 inhibitors [ 14 , 15 ], the molecules likely to establish at least one hydrogen bond with backbone groups in the middle of the hinge region (Ala1950) were considered only for experimental analysis using the associated interatomic distance limit of 3.5 Å. As a result, a total of 429 molecules were selected as final virtual hits for the G2019S mutant of LRRK2.…”

“…This kind of simultaneous binding to the hinge region and the P-loop may explain the submicromolar inhibitory activities of Inhibitors 1 – 6 . Direct interactions with the backbone groups in the hinge region and the hydrophobic sidechains of the P-loop were also implicated in the precedent molecular modeling studies on binding of the potent inhibitors of LRRK2 [ 13 , 14 , 15 ].…”

“…Nonetheless, structurally diverse inhibitors of LRRK2 have been identified over the past decade. A great deal of scientific endeavors have led to the discovery of novel potent inhibitors involving aminoquinazoline [ 13 ], pyrazole biaryl sulfonamide [ 14 ], pyrrolo [2,3-d]pyrimidine [ 15 ], constrained peptide [ 16 ], proteolysis targeting chimera [ 17 ], benzothiazole [ 18 ], azaindazole [ 19 , 20 ], 4,7-dihydrotetrazolo [1,5- a ]pyrimidine [ 21 ], N-pyridazinylbenzamide [ 22 ], 4-ethoxy-7H-pyrrolo [2,3- d ]pyrimidin-2-amine [ 23 ], 3-(4-pyrimidinyl) indazole [ 24 ], 2-aminopyridine [ 25 ], indolinone [ 26 ], triazolopyridazine [ 27 ], and 2-anilino-4-methylamino-5-chloropyrimidine [ 28 ] as the key structural elements. Although the majority of LRRK2 inhibitors have been identified through the screening of a chemical library or chemical derivatizations of the known inhibitor scaffolds, several rational drug design methods have also been applied using various molecular modeling techniques [ 29 , 30 , 31 ].…”

Development of mutation-selective LRRK2 kinase inhibitors as precision medicine for Parkinson's disease and other diseases for which carriers are at increased risk

“…Although molecular modeling efforts based on such G2019S-LRRK2 surrogates have resulted in extremely selective compounds, such as (3) ( 44 ) and (4) ( 45 ), selectivity toward G2019S appears to be amplified in the whole organism ( 43 – 45 ); thus, specific assay techniques may be required to ascertain true compound selectivity. The combined forces of molecular modeling, screening, and iterative compound synthesis have allowed for the successful design of selective G2019S-LRRK2 kinase inhibitor( 44 , 45 ).…”