The electronic structure of the ion pair states of molecular iodine

The electronic configurations of molecular states of iodine are studied through the Optical- Optical Double Resonance excitation of the ion pair states in low vibrational levels. The two photon OODR excitation of ungerade IP states from the gerade ground state is rationalised and the strength of u/g coupling at the intermediate step interpreted in terms of a hyperfine interaction first described by Broyer et al. The potential function of the cl₉(ab) gerade coupling partner in the hyperfine Hamiltonian is derived, along with the lowest levels of a new IP state in the second cluster, the H1ᵤ(2) state. An OODR excitation scheme for populating the Oᵤ⁻(2) IP state is proposed and the dominant component of the cl₉(ab) state configuration is found for R≈5.5Å.A rationalisation for the observed energy ordering of the states within an ion pair cluster is proposed.The radiative lifetimes of nine IP states in low vibrational levels are determined and combined with the relative fluorescent intensities of the IP→Valence charge transfer transitions to derive the Einstein A-coefficients for all the strong transitions from these IP states. A theoretical model is developed in terms of a separated atom description for the electronic configurations of these states and is used to predict the relative dipole strengths of the IP→Valence transitions. The Einstein A-coefficients are then interpreted to give the electronic configurations of the IP states around Rₑᴵᴾ and the relative strengths of the transition dipoles for Pα ↔ Pα, and pπ ↔ pπ electron transfer between ionic centres. A significant difference from the free ion configurations is found with the lowest energy IP states of a given symmetry adopting as low a pα occupancy at the cationic centre as the inter-electron repulsion and spin -orbit energies will allow. This stabilisation is driven by the field gradient due to the anionic charge. The model for the charge transfer transition accounts for the large difference in the summed dipole strengths that is observed for some u/g pairs, even though they have closely similar electronic configurations, and using this model the radiative intensities are shown to be consistent with results from other techniques that probe the electronic structure of IP states. The transition dipole function for the F0ᵤ⁺ (2) ---> X0₉⁺(aa) transition is established over the range 3.13≤R≤4.12Å and its form interpreted in terms of the same electron transfer model. The inferred changes in the electronic configuration of the F0ú (2) state with internuclear separation are shown to be consistent with experimental results for related transitions and with ab initio calculations from other research groups

Biomarker-Directed Targeted Therapy Plus Durvalumab in Advanced Non-Small-Cell Lung Cancer: A Phase 2 Umbrella Trial

For patients with non-small-cell lung cancer (NSCLC) tumors without currently targetable molecular alterations, standard-of-care treatment is immunotherapy with anti-PD-(L)1 checkpoint inhibitors, alone or with platinum-doublet therapy. However, not all patients derive durable benefit and resistance to immune checkpoint blockade is common. Understanding mechanisms of resistance—which can include defects in DNA damage response and repair pathways, alterations or functional mutations in STK11/LKB1, alterations in antigen-presentation pathways, and immunosuppressive cellular subsets within the tumor microenvironment—and developing effective therapies to overcome them, remains an unmet need. Here the phase 2 umbrella HUDSON study evaluated rational combination regimens for advanced NSCLC following failure of anti-PD-(L)1-containing immunotherapy and platinum-doublet therapy. A total of 268 patients received durvalumab (anti-PD-L1 monoclonal antibody)–ceralasertib (ATR kinase inhibitor), durvalumab–olaparib (PARP inhibitor), durvalumab–danvatirsen (STAT3 antisense oligonucleotide) or durvalumab–oleclumab (anti-CD73 monoclonal antibody). Greatest clinical benefit was observed with durvalumab–ceralasertib; objective response rate (primary outcome) was 13.9% (11/79) versus 2.6% (5/189) with other regimens, pooled, median progression-free survival (secondary outcome) was 5.8 (80% confidence interval 4.6–7.4) versus 2.7 (1.8–2.8) months, and median overall survival (secondary outcome) was 17.4 (14.1–20.3) versus 9.4 (7.5–10.6) months. Benefit with durvalumab–ceralasertib was consistent across known immunotherapy-refractory subgroups. In ATM-altered patients hypothesized to harbor vulnerability to ATR inhibition, objective response rate was 26.1% (6/23) and median progression-free survival/median overall survival were 8.4/22.8 months. Durvalumab–ceralasertib safety/tolerability profile was manageable. Biomarker analyses suggested that anti-PD-L1/ATR inhibition induced immune changes that reinvigorated antitumor immunity. Durvalumab–ceralasertib is under further investigation in immunotherapy-refractory NSCLC

A novel systemically administered toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models

Although topical TLR7 therapies such as imiquimod have proved successful in the treatment of dermatological malignancy, systemic delivery may be required for optimal immunotherapy of nondermatological tumors. We report that intravenous delivery of the novel small molecule TLR7 agonist, DSR-6434, leads to the induction of type 1 interferon and activation of T and B lymphocytes, NK and NKT cells. Our data demonstrate that systemic administration of DSR-6434 enhances the efficacy of ionizing radiation (IR) and leads to improved survival in mice bearing either CT26 or KHT tumors. Of the CT26 tumor-bearing mice that received combined therapy, 55% experienced complete tumor resolution. Our data reveal that these long-term surviving mice have a significantly greater frequency of tumor antigen specific CD8(+) T cells when compared to age-matched tumor-naïve cells. To evaluate therapeutic effects on spontaneous metastases, we showed that combination of DSR-6434 with local IR of the primary tumor significantly reduced metastatic burden in the lung, when compared to time-matched cohorts treated with IR alone. The data demonstrate that systemic administration of the novel TLR7 agonist DSR-6434 in combination with IR primes an antitumor CD8(+) T-cell response leading to improved survival in syngeneic models of colorectal carcinoma and fibrosarcoma. Importantly, efficacy extends to sites outside of the field of irradiation, reducing metastatic load. Clinical evaluation of systemic TLR7 therapy in combination with IR for the treatment of solid malignancy is warranted. WHAT'S NEW? Recent evidence suggests that damage from ionizing radiation (IR) can render tumor cells immunogenic. Unfortunately, established tumors often suppress this anti-tumor immune response. Combination therapy with IR and immune-modulators such as Toll-like-receptor (TLR) family agonists may overcome this problem. In this proof-of-concept study, the authors examined one such small-molecule drug, called DSR-6434. They found that systemic administration of DSR-6434 can enhance the effectiveness of radiotherapy in mice, and that this occurs via the generation of tumor-specific immune responses. Easily delivered drugs that activate TLR-family molecules may thus offer a promising therapeutic approach

Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy.

Strategies to augment anti-cancer immune responses have recently demonstrated therapeutic utility. To date clinical success has been achieved through targeting co-inhibitory checkpoints such as CTLA-4, PD-1, and PD-L1. However, approaches that target co-activatory pathways are also being actively being developed. Here we report that the novel TLR7-selective agonist DSR-29133 is well tolerated in mice and leads to acute immune activation. Administration of DSR-29133 leads to the induction of IFNα/γ, IP-10, TNFα, IL-1Ra and IL-12p70, and to a reduction in tumor burden in syngeneic models of renal cancer (Renca), metastatic osteosarcoma (LM8) and colorectal cancer (CT26). Moreover, we show that the efficacy of DSR-29133 was significantly improved when administered in combination with low-dose fractionated radiotherapy (RT). Effective combination therapy required weekly administration of DSR-29133 commencing on day 1 of a fractionated RT treatment cycle, whereas no enhancement of radiation response was observed when DSR-29133 was administered at the end of the fractionated RT cycle. Combined therapy resulted in curative responses in a high proportion of mice bearing established CT26 tumors which was dependent on the activity of CD8(+) T-cells but independent of CD4(+) T-cells and NK/NKT cells. Moreover, long-term surviving mice originally treated with DSR-29133 and RT were protected by a tumor-specific memory immune response which could prevent tumor growth upon rechallenge. These results demonstrate that DSR-29133 is a potent selective TLR7 agonist that when administered intravenously can induce anti-tumor immune responses that can be further enhanced through combination with low-dose fractionated RT

Structure-based design of 2-arylamino-4-cyclohexylmethyl-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2

A series of O4-cyclohexylmethyl-5-nitroso-6-aminopyrimidines bearing 2-arylamino substituents was synthesised and evaluated for CDK1 and CDK2 inhibitory activity. Consistent with analogous studies with O6-cyclohexylmethylpurines, 2-arylaminopyrimidines with a sulfonamide or carboxamide group at the 40-position were potent inhibitors, with IC50 values against CDK2 of 1.1±10.3 and 34±8 nM, respectively. The crystal structure of the 40-carboxamide derivative, in complex with phospho-Thr160 CDK2/cyclin A, confirmed the expected binding mode of the inhibitor, and revealed an additional interaction between the carboxamide function and an aspartate residue

8‑Substituted <i>O</i>⁶‑Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode

Evaluation of the effects of purine <i>C</i>-8 substitution within a series of CDK1/2-selective <i>O</i>⁶-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that <i>C</i>-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9<i>H</i>-purine adopts a “reverse” binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an <i>ortho</i>-tolyl or <i>ortho</i>-chlorophenyl group at the purine C-8 position restored the potency of these “reverse” binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9<i>H</i>-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography

Discovery of 4‑{4-[(3<i>R</i>)‑3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}‑1<i>H</i>‑indole (AZ20): A Potent and Selective Inhibitor of ATR Protein Kinase with Monotherapy in Vivo Antitumor Activity

ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound <b>6</b> (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC₅₀ of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC₅₀ of 50 nM. Compound <b>6</b> potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses <b>6</b> leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound <b>6</b> is a useful compound to explore ATR pharmacology in vivo