Borna Zandkarimi

Activating mutations in the Kirsten rat sarcoma (KRAS) gene are prevalent oncogenic drivers in nonsmall cell lung cancer (NSCLC). Patients harboring KRAS-mutant lung cancers frequently develop central nervous system (CNS) metastases. Although approved KRAS G12C inhibitors (i.e., sotorasib and adagrasib) show promising clinical CNS activity, these agents demonstrate low preclinical brain-to-plasma ratios, raising the question of whether compounds with elevated preclinical Kp,uu,brain values might show enhanced clinical performance. Here, we report the first successful application of DNA-encoded library (DEL) screening technology to the identification of CNS-penetrant covalent inhibitors of KRAS G12C. In this effort, a property-biased covalent DEL-screening approach enabled the discovery of a structurally novel series of hydrogen bond donor-free KRAS G12C inhibitors with improved CNS exposure. Leveraging structure-based design, we refined this hit series to deliver lead compound AM-8719, a CNS-penetrant, orally efficacious KRAS G12C inhibitor exhibiting 200-fold improved potency with respect to initial screening hits.

Ethylene is a key molecule in the chemical industry and it can be obtained through the catalytic dehydrogenation of ethane. Pt‐based catalysts show high performance toward alkane dehydrogenation, but suffer from coke formation and sintering that deactivate the catalyst. Ge was recently discovered to be a promising alloying element that suppresses deactivation of Pt while preserving its catalytic activity toward alkane dehydrogenation. This work explores the effect of the Ge content in supported PtGe cluster alloys, on the activity toward ethane dehydrogenation, selectivity against deeper dehydrogenation and coking, and sintering resistance. The model proposed herein is a tetrameric Pt cluster supported on magnesia, with varying amounts of added Ge. The phase diagram for these clusters was computed using global optimization at the density functional theory level, and under the paradigm of a statistical ensemble of many states populated by clusters at catalytic temperatures. The phase diagram shows that various Ge contents should be synthetically accessible, with Pt₄Ge/MgO and Pt₄Ge₄/MgO being the most likely phases. The subsequent adsorption and mechanistic studies show that the clusters with the 1 : 4 Ge to Pt ratio (Pt₄Ge/MgO) feature the largest resistance to sintering and best selectivity in the ethane dehydrogenation toward ethylene. Clusters without Ge are too active and easily coke, whereas clusters with higher Ge content start losing the catalytic activity toward ethane dehydrogenation. Thus, Ge concentration is a lever of control of Pt cluster stability and selectivity, and of cluster catalyst design. The effect of the Ge concentration on the cluster properties is explained on the basis of the electronic structure.

Size selection was demonstrated to suppress Ostwald ripening of supported catalytic nanoparticles. When the supported clusters are subnanometer in size and highly fluxional, such as Pt clusters on the rutile TiO₂(110) surface, this paradigm breaks down, and the established theory of sintering needs a revision. At temperatures characteristic of catalysis (i.e. 700 K), sub‐nano clusters thermally populate many low‐energy metastable isomers. As these isomers all have different geometric and electronic structures, and thus, formation and dissociation energies (in lieu of surface energy), Ostwald ripening is not suppressed, despite the size‐selection. However, some clusters arise as magic numbers in terms of sintering stability at the ensemble level. Acceleration of sintering by metastable species persists though weakens in polydisperse cluster systems. We propose a competing pathways theory for sintering, which at the atomistic level describes the found size‐specific sintering behavior.

Size selection was demonstrated to suppress Ostwald ripening of supported catalytic nanoparticles. When the supported clusters are subnanometer in size and highly fluxional, such as Pt clusters on the rutile TiO₂(110) surface, this paradigm breaks down, and the established theory of sintering needs a revision. At temperatures characteristic of catalysis (i.e. 700 K), sub‐nano clusters thermally populate many low‐energy metastable isomers. As these isomers all have different geometric and electronic structures, and thus, formation and dissociation energies (in lieu of surface energy), Ostwald ripening is not suppressed, despite the size‐selection. However, some clusters arise as magic numbers in terms of sintering stability at the ensemble level. Acceleration of sintering by metastable species persists though weakens in polydisperse cluster systems. We propose a competing pathways theory for sintering, which at the atomistic level describes the found size‐specific sintering behavior.

X-ray absorption near edge structure (XANES) spectroscopy is widely used for operando catalyst characterization. We show that, for highly fluxional supported nanoclusters, the customary extraction of the oxidation state of the metal from the XANES data by fitting to the bulk standards is highly questionable. The XANES signatures, as well as the apparent oxidation state for such clusters arise from a complex combination of many factors, and not only from the chemical composition in reaction conditions (e.g. oxygen content in oxidizing astrosphere). The thermally-accessible isomerization and population of several structurally distinct cluster forms, cluster-support interaction, and intrinsic size effects all impact the metal oxidation state and XANES signal. We demonstrate this on copper oxide clusters with different compositions, Cu4Ox(x = 2–5) and Cu5Oy (y = 3, 5), deposited on amorphous alumina and ultrananocrystalline diamond (UNCD), for which we computed the XANES spectra and compare the results to the experiment. We show in addition that fitting the experimental spectrum to calculated spectra of supported clusters can in contrast provide good agreement and insight on the spectrum-composition-structure relation. Experimental XANES interpreted using the proposed fitting scheme shows the partial reduction of Cu oxide clusters at rising temperatures, and pinpoints the specific stoichiometries that dominate in the ensemble of cluster states as the temperature changes.

Heterogeneous catalysis is at the heart of the chemical industry. Being able to tune and design efficient catalysts for processes of interest is of the utmost importance, and for this, a molecular-level understanding of heterogeneous catalysts is the first step and indeed a prime focus of modern catalysis research. For a long time, the single most thermodynamically stable structure of the catalytic interface attained under the reaction conditions had been envisioned as the reactive phase. However, some catalytic interfaces continue to undergo structural dynamics in the steady state, triggered by high temperatures and pressures and binding and changing reagents. Among particularly dynamic interfaces are such widely used catalysts as crystalline and amorphous surfaced supporting (sub)nanometallic clusters. Recently, it became clear that this dynamic fluxionality causes the supported clusters to populate many distinct structural and stoichiometric states under catalytic conditions. Hence, the catalytic interface should be viewed as an evolving statistical ensemble of many structures (rather than one structure). Every member in the ensemble contributes to the properties of the catalyst differently, in proportion to its probability of being populated. This new notion flips the established paradigm and calls for a new theory, new modeling approaches, operando measurements, and updated design strategies. The statistical ensemble nature of surface-supported subnanocluster catalysts can be exemplified by oxide-supported and adsorbate-covered Pt, Pd, Cu, and CuPd clusters, which are catalytic toward oxidative and nonoxidative dehydrogenation. They have access to a variety of 3D and quasi-2D shapes. The compositions of their thermal ensembles are dependent on the cluster size, leading to size-specific catalytic activities and the famous “every atom counts” phenomenon. The support and adsorbates affect catalyst structures, and the state of the reacting species causes the ensemble to change in every reaction intermediate. The most stable member of the ensemble dominates the thermodynamic properties of the corresponding intermediate, whereas the kinetics can be determined by more active but less populated metastable catalyst states, and that suggests that many earlier studies might have overlooked the actual active sites. Both effects depend on the relative time scales of catalyst restructuring and reaction dynamics. The catalyst may routinely operate off-equilibrium. Ensemble phenomena lead to surprising exceptions from established rules of catalysis, such as scaling relations and Arrhenius behavior. Catalyst deactivation is also an ensemble property, and its extent of mitigation can be predicted through the new paradigm. These findings were enabled by advances in theory, such as global optimization and subsequent utilization of multiple local minima and pathways sampling as well as operando catalyst characterization. The fact that the per-site and per-species resolution is needed for the description and prediction of catalyst properties gives theory the central role in catalysis research, as most experiments provide ensemble-average information and cannot detect the crucial minority species that may be responsible for the catalytic activity.

An atomic layer deposition process is used to modify size-selected Pt₇/alumina model catalysts by Sn addition, both before and after Pt₇ cluster deposition. Surface science methods are used to probe the effects of Sn-modification on the electronic properties, reactivity, and morphology of the clusters. Sn addition, either before or after cluster deposition, is found to strongly affect the binding properties of a model alkene, ethylene, changing the number and type of binding sites, and suppressing decomposition leading to carbon deposition and poisoning of the catalyst. Density functional theory on a model system, Pt₄Sn₃/alumina, shows that the Sn and Pt atoms are mixed, forming alloy clusters with substantial electron transfer from Sn to Pt. The presence of Sn also makes all the thermally accessible structures closed shell, such that ethylene binds only by π-bonding to a single Pt atom. The Sn-modified catalysts are quite stable in repeated ethylene temperature programmed reaction experiments, suggesting that the presence of Sn also reduces the tendency of the sub-nano-clusters to undergo thermal sintering.

It has recently been shown that the dynamic behavior of surface‐supported nanocluster catalysts in realistic reaction conditions defies conventional models used in catalysis. This opens new doors in catalysis by giving more leverage in catalyst design, but also requires a major revision of the understanding of how dynamic heterogeneous catalytic interfaces operate, as well as of the computational approaches of catalyst modeling, and experimental methods of catalyst characterization. Major aspects of the new paradigm include the collective action of many catalyst states that form a statistical ensemble in reaction conditions, the catalytic activity and selectivity being driven by rare and metastable catalyst states, reaction thermodynamics and kinetics being controlled by different states of the catalyst, broken scaling relationships, non‐Arrhenius behaviors, and catalyst dynamic restructuring being an essential part of the reaction mechanism. For computation, this complexity means the departure from the standard density functional theory calculations of reaction mechanisms on a single catalyst structure. For experiment, it calls for the development of operando characterization tools with the per‐site resolution and the ability to find the minority sites that govern the catalytic activity. For catalyst design, the goal becomes the creation of the catalyst state (geometric and electronic) that might not be present in the as‐prepared catalyst, but would develop in the reaction conditions and would have the desired activity then. While cluster catalysts are the most dramatic in their dynamic fluxionality, other amorphous interfaces also exhibit some of it, and thus are also subject to similar paradigm revision.This article is categorized under: Structure and Mechanism > Reaction Mechanisms and Catalysis