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Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683). High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro - in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs. An orally available VHL-ERα PROTAC was developed that showed excellent degradation in vitro. When dosing in vivo, the degradation of ERα was lower than expected, due to competitive binding at the ERα binding site between the PROTAC and a linker metabolite.

Improvements were made in the synthesis of N-(E-but-2-en-1-yl)-4-hydroxy-4-(indol-2-yl)but-1-ylamine 102, by modification of the protecting group of the amino-acetal 111. An alternative route to 102 via N-(4-oxo-4-(1-phenylsulfonylindol-2-yl)but-1-yl)phenylsulfonamide 133 was developed which allowed access to the ketones 114 and 134, precursors suitable for cyclisation to the ABCD framework of apparicine. Extension of this route to introduction of an N-iodobutenyl moiety was unsuccessful. Cyclisation of the ketones was attempted using a variety of metal-catalysed coupling reactions. Further modification of 114 into a species suitable for elaboration of the D-ring was undertaken. Attempted synthesis of the epoxy-ketone 255 and cyclisation of the N-dibromobutyl ketones 254 and 260 was unsuccessful. Synthesis of the iodobutenyl diene 136 was achieved via the N-butynylamino-alcohol 188. A route to 136 via the N-iodobutenylamido-aldehyde 174, analogous to the route initially utilised in preparation of the amino-alcohol 102, was unsuccessful however. Attempted Na-Phenylsulfonylation of the dihydro-3H-pyrrolylindole 86 resulted in low yields of the novel 1-phenylsulfonyl-3-phenylsulfinyl analogue 200, and phenylsulfinylation of indole and pyrrole was achieved. Ring-opening of the N-crotyl salt 194 with base could not be brought about. Treatment with acetic acid led to the ring-opened diacetyl product 212.

X-ray free-electron lasers can generate radiation pulses with extreme peak intensities at short wavelengths. This enables the investigation of laser–matter interactions in a regime of high fields, yet at a non-relativistic ponderomotive potential, where ordinary rules of light–matter interaction may no longer apply and nonlinear processes are starting to become observable. Despite small cross-sections, first nonlinear effects in the hard x-ray regime have recently been observed in solid targets, including x-ray-optical sum-frequency generation (XSFG), x-ray second harmonic generation (XSHG) and two-photon Compton scattering (2PCS). Nonlinear interactions of bound electrons in the x-ray range are fundamentally different from those dominating at optical frequencies. Whereas in the optical regime nonlinearities are predominantly caused by anharmonicities of the atomic potential in the chemical bonds, x-ray nonlinearities far above atomic resonances are expected to be due to nonlinear oscillations of quasi-free electrons, including inner-shell atomic electrons. While the quasi-free-electron model agrees reasonably well with the experimental data for XSFG and XSHG, 2PCS measurements have led to unexpected results: the energy of the nonlinearly scattered photons from non-relativistic electrons shows a substantial unexpected red shift in addition to the Compton shift that is well beyond that predicted by a nonlinear quantum electrodynamics model for free electrons. A potential explanation for the spectral broadening is based on a previously unexplored scattering process that involves the whole atom rather than just quasi-free electrons. A first simulation that includes the atomic binding potential was successful in describing a broadening of the spectrum of the nonlinearly scattered photons to longer wavelengths for soft x-rays. However, the same model does not show any broadening at hard x-ray wavelengths, which is in agreement with other simulation approaches. To this point no calculation has been able to reproduce the experimentally observed broadening. Here we present further experimental data of 2PCS for an extended parameter range using additional diagnostics. In particular, we present measurements of the electron momentum distribution during the interaction that strongly suggest that the spectral broadening is not caused by an increased plasma temperature. We extend our measurement of the magnitude of the red shift in beryllium to > 1.9 k e V in addition to the Compton shift expected for free electrons and expand the measurement of the angular distribution to include forward scattering angles. We also present first measurements of 2PCS from diamond.

Radiation reaction, the force experienced by an accelerated charge due to radiation emission, has long been the subject of extensive theoretical and experimental research. Experimental verification of a quantum, strong-field description of radiation reaction is fundamentally important, and has wide-ranging implications for astrophysics, laser-driven particle acceleration, next-generation particle colliders and inverse-Compton photon sources for medical and industrial applications. However, the difficulty of accessing regimes where strong field and quantum effects dominate inhibited previous efforts to observe quantum radiation reaction in charged particle dynamics with high significance. We report a high significance ( > 5 σ ) observation of strong-field radiation reaction on electron spectra where quantum effects are substantial. We obtain quantitative, strong evidence favouring the quantum-continuous and quantum-stochastic models over the classical model; the quantum models perform comparably. The lower electron energy losses predicted by the quantum models account for their improved performance. Model comparison was performed using a novel Bayesian framework, which has widespread utility for laser-particle collision experiments, including those utilising conventional accelerators, where some collision parameters cannot be measured directly. Radiation reaction (RR) on particles in strong fields is the subject of intense experimental research, but previous efforts lacked statistical significance due to the extreme regimes required. Here, the authors report a 5 σ observation of RR and obtain strong, quantitative evidence favouring quantum models over classical, using an all-optical setup where electrons are accelerated by a laser in a gas jet before colliding with a second, intense pulse.

Abstract Laser wakefield accelerators commonly produce on-axis, low-divergence, high-energy electron beams. However, a high charge, annular shaped beam can be trapped outside the bubble and accelerated to high energies. Here we present a parametric study on the production of low-energy-spread, ultra-relativistic electron ring beams in a two-stage gas cell. Ring-shaped beams with energies higher than 750 MeV are observed simultaneously with on axis, continuously injected electrons. Often multiple ring shaped beams with different energies are produced and parametric studies to control the generation and properties of these structures were conducted. Particle tracking and particle-in-cell simulations are used to determine properties of these beams and investigate how they are formed and trapped outside the bubble by the wake produced by on-axis injected electrons. These unusual femtosecond duration, high-charge, high-energy, ring electron beams may find use in beam driven plasma wakefield accelerators and radiation sources.