Introduction: Novel rearranged in transfection (RET)-specific tyrosine kinase inhibitors (TKIs) such as selpercatinib (LOXO-292) have shown unprecedented efficacy in tumors positive for RET fusions or mutations, notably RET fusionpositive NSCLC and RET-mutated medullary thyroid cancer (MTC). However, the mechanisms of resistance to these agents have not yet been described.

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The mechanisms of oxidations of amines, sulfides, and alkenes by peroxynitrous acid, as well as the mechanism for the conversion of peroxynitrous acid to nitric acid, have been investigated with density functional theory methods using the Becke3LYP functional and the 6-31G* basis set. Theoretical evidence is obtained for the mechanisms and transition states of oxidations by peroxynitrous acid both by one- and two-electron processes. Transition structures for two-electron oxidations of amines, sulfides, and alkenes are reported. An activated form of peroxynitrous acid, HOONO*, is often invoked to account for the potent oxidative chemistry of peroxynitrous acid and derivatives; a structure with the appropriate characteristics has been located. The structure of the CO2 adduct of peroxynitrite is also explored, and a mechanistic scheme is proposed for the acceleration of peroxynitrite oxidations in the presence of CO2. Energetics are described in detail for each of these species and oxidation transition structures.

The transition structures for the epoxidations of ethylene by performic acid, dioxirane, oxaziridine, and peroxynitrous acid have been located with density functional theory methods using the Becke3LYP functional and 6-31G* basis set. All of the epoxidations have spiro transition states; those with performic acid and dioxirane are early and involve synchronous oxygen transfer, while those with oxaziridine and peroxynitrous acid are later with asynchronous oxygen transfer. The results from Becke3LYP/6-31G* theory are compared with MP2/6-31G* literature values. Substitution on ethylene by methoxy, methyl, vinyl, and cyano groups changes the transition state geometries toward asynchronous spiro structures. The activation energies are lowered by all substituents except the cyano group in reactions of performic acid and dioxirane. Experimental stereoselectivities are rationalized by using transition structure models based upon these transition structures.

HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

Potent inhibitors of 7,8-dihydroneopterin aldolase (DHNA; EC 4.1.2.25) have been discovered using CrystaLEAD X-ray crystallographic high-throughput screening followed by structure-directed optimization. Screening of a 10 000 compound random library provided several low affinity leads and their corresponding X-ray crystal structures bound to the enzyme. The presence of a common structural feature in each of the leads suggested a strategy for the construction of a directed library of approximately 1000 compounds that were screened for inhibitory activity in a traditional enzyme assay. Several lead compounds with IC(50) values of about 1 microM against DHNA were identified, and crystal structures of their enzyme-bound complexes were obtained by cocrystallization. Structure-directed optimization of one of the leads thus identified afforded potent inhibitors with submicromolar IC(50) values.

We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.

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