E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To ...understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.
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•DCAF15-sulfonamide binds to RBM39 through a single α helix of RBM39•The structure reveals how a sulfonamide molecular glue recruits RBM39 to DCAF15•Both RBM39 and E7820 have weak affinity to DCAF15 individually•Synergistic binding to DCAF15 leads to the formation of stable ternary complex
Du et al. describe in structural and kinetic detail how a sulfonamide glue, E7820, recruits RBM39 to DCAF15, a CUL4-related E3 ubiquitin ligase. RBM39 and E7820 each has weak affinity to DCAF15; however, synergistic binding of the two to DCAF15 leads to the formation of a stable ternary complex.
The hypoxia-inducible factor 2α (HIF-2α) is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC). Our first HIF-2α inhibitor PT2385 demonstrated promising proof of concept clinical ...activity in heavily pretreated advanced ccRCC patients. However, PT2385 was restricted by variable and dose-limited pharmacokinetics resulting from extensive metabolism of PT2385 to its glucuronide metabolite. Herein we describe the discovery of second-generation HIF-2α inhibitor PT2977 with increased potency and improved pharmacokinetic profile achieved by reduction of phase 2 metabolism. Structural modification by changing the geminal difluoro group in PT2385 to a vicinal difluoro group resulted in enhanced potency, decreased lipophilicity, and significantly improved pharmacokinetic properties. In a phase 1 dose-escalation study, the clinical pharmacokinetics for PT2977 supports the hypothesis that attenuating the rate of glucuronidation would improve exposure and reduce variability in patients. Early evidence of clinical activity shows promise for PT2977 in the treatment of ccRCC.
Weaving an intricate web: A stereoselective synthesis of (-)-agelastatin A has been developed, which requires 11 steps from commercially available starting material. The application of a Rh-catalyzed ...intramolecular olefin aziridination reaction and the subsequent manipulation of the resulting tricyclic intermediate (see scheme) punctuate this study.
HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the ...overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*
interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC
= 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.
HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the ...overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel–Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*Ar interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC50 = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.
The manzacidins represent a small family of structurally unique secondary metabolites found only sparingly in nature. Efforts to probe the pharmacological profile of these intriguing bromopyrrole ...alkaloids have been precluded by a deficiency of available material. Access to substantive quantities of both manzacidins A and C is now made possible through a rapid, enantioselective, and highly efficient synthesis that is described herein. The path to these targets showcases for the first time the distinct power of our catalytic C−H bond amination methodology for simplifying problems in alkaloid total synthesis. Application of this chemistry enables the facile and enantiospecific installation of tetrasubstituted carbinolamine stereocenters, functionality common to all of the manzacidins. The requisite materials for implementing our plan are assembled using modern tools for catalytic asymmetric synthesis that include both carbonyl-ene and directed hydrogenation reactions. In addition, a new protocol for tetrahydropyrimidine synthesis is established. The synthesis of each manzacidin comprises a 10-step sequence that proceeds in an overall yield of ∼30%.
Benzene-fused cyclic sulfamates are prepared from ortho-substituted phenolic starting materials through selective C−H amination or olefin aziridination. These unique heterocycles will engage in ...Ni-catalyzed cross-coupling reactions with aryl- and alkyl-Grignard reagents. Application of modern tools for C−N and C−C bond formation thus makes readily available functional amine derivatives and augments the possible uses for C−H amination in synthesis.
Oxidative C−H amination of chiral sulfamate esters using achiral Rh-carboxylate catalysts, PhI(OAc)2, and MgO occurs in high yield and with good to excellent diastereocontrol. A number of examples ...are included to support a proposed transition state model that accounts for the observed stereoinduction. In addition, stereoselective intramolecular aziridination with substituted homoallyl sulfamates is demonstrated and is rationalized through an analogous stereochemical construct.
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