Design and Synthesis of Novel Cereblon Binders for Use in Targeted Protein Degradation.

Modulating the chemical composition of cereblon (CRBN) binders is a critical step in the optimization process of protein degraders that seek to hijack the function of this E3 ligase. Small structural changes can have profound impacts on the overall profile of these compounds, including depth of on-target degradation, neosubstrate degradation selectivity, as well as other drug-like properties. Herein, we report the design and synthesis of a series of novel CRBN binding moieties. These CRBN binders were evaluated for CRBN binding and degradation of common neosubstrates Aiolos and GSPT1. A selection of these binders was employed for an exploratory matrix of heterobifunctional molecules, targeting CRBN-mediated degradation of the androgen receptor.

Importance of CAR-T cell therapy monitoring using high-throughput assays.

Advances in the development of chimeric antigen receptor (CAR)-T cells have undermined the paramount importance of this technology for the success of adoptive T-cell immunotherapy. The bespoke production of autologous CAR-T cells is a lengthy and costly process. Thus, the development of more cost-effective allogeneic 'off-the-shelf' CAR-T cells provides a more readily available treatment option. The exploration of methods to reduce costs and to determine which CAR-T cells are the most effective is key for providing this breakthrough treatment to most patients. The process from the design and development of CAR-T cells, through pre-clinical and clinical testing and manufacturing, to patient monitoring involves a variety of high-throughput tools that enable the monitoring of all processes to ensure the safety and efficacy of the treatment.

CC-90009: A Cereblon E3 Ligase Modulating Drug That Promotes Selective Degradation of GSPT1 for the Treatment of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.

Human-mediated dispersal and disturbance shape the metapopulation dynamics of a long-lived herb.

As anthropogenic impacts on the natural world escalate, there is increasing interest in the role of humans in dispersing seeds. But the consequences of this Human-Mediated Dispersal (HMD) on plant spatial dynamics are little studied. In this paper, we ask how secondary dispersal by HMD affects the dynamics of a natural plant metapopulation. In addition to dispersal between patches, we suggest within-patch processes can be critical. To address this, we assess how variation in local population dynamics, caused by small-scale disturbances, affects metapopulation size. We created an empirically based model with stochastic population dynamics and dispersal among patches, which represented a real-world, cliff-top metapopulation of wild cabbage Brassica oleracea. We collected demographic data from multiple populations by tagging plants over eight years. We assessed seed survival, and establishment and survival of seedlings in intact vegetation vs. small disturbances. We modeled primary dispersal by wind using field data and used experimental data on secondary HMD by hikers. We monitored occupancy patterns over a 14-yr period in the real metapopulation. Disturbance had large effects on local population growth rates, by increasing seedling establishment and survival. This meant that the modeled metapopulation grew in size only when the area disturbed in each patch was above 35%. In these growing metapopulations, although only 0.2% of seeds underwent HMD, this greatly enhanced metapopulation growth rates. Similarly, HMD allowed more colonizations in declining metapopulations under low disturbance, and this slowed the rate of decline. The real metapopulation showed patterns of varying patch occupancy over the survey years, which were related to habitat quality, but also positively to human activity along the cliffs, hinting at beneficial effects of humans. These findings illustrate that realistic changes to dispersal or demography, specifically by humans, can have fundamental effects on the viability of a species at the landscape scale.

Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma.

Many patients with multiple myeloma (MM) initially respond to treatment with modern combination regimens including immunomodulatory agents (lenalidomide and pomalidomide) and proteasome inhibitors. However, some patients lack an initial response to therapy (i.e., are refractory), and although the mean survival of MM patients has more than doubled in recent years, most patients will eventually relapse. To address this need, we explored the potential of novel cereblon E3 ligase modulators (CELMoDs) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). We found that optimization beyond potency of degradation, including degradation efficiency and kinetics, could provide efficacy in a lenalidomide-resistant setting. Guided by both phenotypic and protein degradation data, we describe a series of CELMoDs for the treatment of RRMM, culminating in the discovery of CC-92480, a novel protein degrader and the first CELMoD to enter clinical development that was specifically designed for efficient and rapid protein degradation kinetics.

Human-mediated dispersal of seeds over long distances.

Human activities have fundamental impacts on the distribution of species through altered land use, but also directly by dispersal of propagules. Rare long-distance dispersal events have a disproportionate importance for the spread of species including invasions. While it is widely accepted that humans may act as vectors of long-distance dispersal, there are few studies that quantify this process. We studied in detail a mechanism of human-mediated dispersal (HMD). For two plant species we measured, over a wide range of distances, how many seeds are carried by humans on shoes. While over half of the seeds fell off within 5m, seeds were regularly still attached to shoes after 5 km. Semi-mechanistic models were fitted, and these suggested that long-distance dispersal on shoes is facilitated by decreasing seed detachment probability with distance. Mechanistic modelling showed that the primary vector, wind, was less important as an agent of long-distance dispersal, dispersing seeds less than 250 m. Full dispersal kernels were derived by combining the models for primary dispersal by wind and secondary dispersal by humans. These suggest that walking humans can disperse seeds to very long distances, up to at least 10 km, and provide some of the first quantified dispersal kernels for HMD.