Lung-restricted ALK5 inhibition avoids systemic toxicities associated with TGFß pathway inhibition.

Systemic therapies targeting transforming growth factor beta (TGFß) or TGFßR1 kinase (ALK5) have been plagued by toxicities including cardiac valvulopathy and bone physeal dysplasia in animals, posing a significant challenge for clinical development in pulmonary indications. The current work aims to demonstrate that systemic ALK5-associated toxicities can be mitigated through localized lung delivery. Lung-selective (THRX-144644) and systemically bioavailable (galunisertib) ALK5 inhibitors were compared to determine whether lung selectivity is sufficient to maintain local tissue concentrations while mitigating systemic exposure and consequent pathway-related findings. Both molecules demonstrated potent ALK5 activity in rat precision cut lung slices (PCLS; p-SMAD3 half-maximal inhibitory concentration [IC50], 141 nM and 1070 nM for THRX-144644 and galunisertib, respectively). In 14-day repeat-dose studies in rats, dose-related cardiac valvulopathy was recapitulated with oral galunisertib at doses ≥150 mg/kg/day. In contrast, inhaled nebulized THRX-144644 did not cause similar systemic findings up to the maximally tolerated doses in rats or dogs (10 and 1.5 mg/kg/day, respectively). THRX-144644 lung-to-plasma ratios ranged from 100- to 1200-fold in rats and dogs across dose levels. THRX-144644 lung trough (24 h) concentrations in rats and dogs ranged from 3- to 17-fold above the PCLS IC50 across tolerated doses. At a dose level exceeding tolerability (60 mg/kg/day; 76-fold above PCLS IC50) minimal heart and bone changes were observed when systemic drug concentrations reached pharmacologic levels. In conclusion, the current preclinical work demonstrates that localized pulmonary delivery of an ALK5 inhibitor leads to favorable TGFß pathway pharmacodynamic inhibition in lung while minimizing key systemic toxicities.

Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors.

MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation.

[socioecological features of the epidemiology of sarcoidosis in the poltava region, Ukraine].

OBJECTIVE: Introduction: Lung sarcoidosis is a systemic granulomatous disease that can affect various organs and systems of a person. Due to the lack of a uniform standardized approach to the diagnosis of sarcoidosis, the epidemiological pattern is heterogeneous and depends on many factors. The aim: To investigate the correlation between the number of patients with sarcoidosis among the population of the Poltava region (Ukraine) and the ecological characteristics of the industrial activity of the region in comparison with the data on the availability of subspecialists in respiratory diseases. PATIENTS AND METHODS: Materials and methods: The study is based on a retrospective analysis of patients with sarcoidosis living in the Poltava region (Ukraine) for the period from 2008 to 2018. RESULTS: Results: The analysis of the correlation between the intensity of environmental impacts on the region and the number of patients with sarcoidosis did not reveal statistically significant changes. An odds ratio (OR) of the occurrence of sarcoidosis among the urban population has not experienced significant dynamics (OR 1,337, 95% CI: 0.96-1.86) compared with those living in rural areas. The number of specialists performing the duties of a pulmonologist in the region is associated with a significantly higher number of registered patients with various forms of sarcoidosis (r=0.27, p=0.04). CONCLUSION: Conclusions: There was no reliable relationship between the risk of sarcoidosis and habitat in areas with increased ecological and industrial load in the Poltava region. The uneven distribution of specialized medical care reduces the patient's odds of establishing a diagnosis of sarcoidosis in the countryside.

A Unifying Synthesis Approach to the C18-, C19-, and C20-Diterpenoid Alkaloids.

The secondary metabolites that comprise the diterpenoid alkaloids are categorized into C18, C19, and C20 families depending on the number of contiguous carbon atoms that constitute their central framework. Herein, we detail our efforts to prepare these molecules by chemical synthesis, including a photochemical approach, and ultimately a bioinspired strategy that has resulted in the development of a unifying synthesis of one C18 (weisaconitine D), one C19 (liljestrandinine), and three C20 (cochlearenine, paniculamine, and N-ethyl-1α-hydroxy-17-veratroyldictyzine) natural products from a common intermediate.

Enyne [4+4] Cycloaddition/Oxidation: Ring Contraction via Cyclopropanones and Their Anionic Ring-Opening Reactions.

Irradiation of a 1,3-enyne tethered to a 2-pyridone, in the presence of oxygen, leads to formation of a seven-membered ring product, an overall [4+4-1] reaction. This transformation involves two unstable intermediates and a sequence of unusual reactions. An initial [4+4] photocycloaddition of the enyne with the pyridone yields a 1,2,5-cyclooctatriene. Photooxidation of this triene forms a cyclopropanone and subsequent photoextrusion of carbon monoxide gives the observed 1,4-cycloheptadiene product. The first-formed cyclooctatriene and the cyclopropanone could be observed and characterized spectroscopically. The cyclopropanone underwent CO extrusion both photochemically and thermally to give the cycloheptadiene product. Addition of fluoride or acetylide to the most stable cyclopropanone occurred chemoselectively at the two different silicon groups rather than the carbonyl group. The resulting cyclopropanone ring openings gave unsaturated aldehydes.

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer.

Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selecti-vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study. SIGNIFICANCE: PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293.

Atropisomeric Racemization Kinetics of MRTX1719 Using Chiral Solvating Agent-Assisted 19F NMR Spectroscopy.

With renewed interest in atropisomerism of drug molecules, efficient methods to experimentally determine torsion rotational energy barriers are needed. Here, we describe use of the chiral phosphoric acid solvating agent (+)-TiPSY to resolve the signals of atropisomers in 19F NMR and to use the data to study the kinetics of racemization and determine the rotational energy barrier of clinical compound MRTX1719. This method is complimentary to traditional chiral high-performance liquid chromatography (HPLC) and enhances the toolkit for chiral analysis techniques.

Fragment optimization and elaboration strategies - the discovery of two lead series of PRMT5/MTA inhibitors from five fragment hits.

Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.

Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers.

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719.

Design and Discovery of MRTX0902, a Potent, Selective, Brain-Penetrant, and Orally Bioavailable Inhibitor of the SOS1:KRAS Protein-Protein Interaction.

SOS1 is one of the major guanine nucleotide exchange factors that regulates the ability of KRAS to cycle through its "on" and "off" states. Disrupting the SOS1:KRASG12C protein-protein interaction (PPI) can increase the proportion of GDP-loaded KRASG12C, providing a strong mechanistic rationale for combining inhibitors of the SOS1:KRAS complex with inhibitors like MRTX849 that target GDP-loaded KRASG12C. In this report, we detail the design and discovery of MRTX0902─a potent, selective, brain-penetrant, and orally bioavailable SOS1 binder that disrupts the SOS1:KRASG12C PPI. Oral administration of MRTX0902 in combination with MRTX849 results in a significant increase in antitumor activity relative to that of either single agent, including tumor regressions in a subset of animals in the MIA PaCa-2 tumor mouse xenograft model.

Stabilization, isomerization and rearrangement of enyne [4 + 4]-cycloadducts.

Reactive 1,2,5-cyclooctatrienes, formed by photocycloaddition of 2-pyridones with enynes, are stabilized by steric shielding, slowing or preventing an otherwise facile [2 + 2]-dimerization reaction. Diisopropylsilyl ether-tethered reactants paired with an alkene substituent (R) produce allenes that are stable (R = TMS) or that isomerize to 1,3-dienes by hydrogen migration (R = alkyl). Under acidic conditions, hydrolysis of the photoproduct's silyl ether can lead to a [3,3]-sigmatropic rearrangement.

Intramolecular pyridone/enyne photocycloaddition: partitioning of the [4 + 4] and [2 + 2] pathways.

Intramolecular photocycloaddition (>290 nm) between a 1,3-enyne and a 2-pyridone is far more selective than the intermolecular version; a three-atom linkage both controls regiochemistry and separates the [2 + 2] and [4 + 4] pathways. All four head-to-head, head-to-tail, tail-to-head, and tail-to-tail tetherings have been investigated. Linkage via the ene of the enyne leads to [2 + 2] products regardless of alkene geometry, whereas linkage through the yne results in [4 + 4] cycloadducts. The bridged 1,2,5-cyclooctatriene products of [4 + 4] cycloaddition are unstable and undergo a subsequent [2 + 2] dimerization reaction.

Enyne [4 + 4] photocycloaddition: bridged 1,2,5-cyclooctatrienes.

Enyne photocycloaddition with a 2-pyridone yields a mixture of products including amide-bridged 1,2,5-cyclooctatrienes, the first examples of enyne [4 + 4] adducts. Four regio- and stereochemical isomers of the [4 + 4] adduct are possible. All appear to be too strained to be isolated, but they have been identified as their [2 + 2] cyclobutane dimers. Cyclobutane and cyclobutene adducts have also been isolated, [2 + 2] addition products possibly related to the unstable [4 + 4] adducts via Cope rearrangement. Calculations suggest that [3,3] rearrangements have high energy barriers, however, making thermal interconversion unlikely.