We present the first measurement of the integrated forward-backward charge asymmetry in top-quark-top-antiquark pair (tt) production in proton-antiproton (pp) collisions in the lepton+jets final ...state. Using a b-jet tagging algorithm and kinematic reconstruction assuming tt + X production and decay, a sample of 0.9 fb(-1) of data, collected by the D0 experiment at the Fermilab Tevatron Collider, is used to measure the asymmetry for different jet multiplicities. The result is also used to set upper limits on tt+X production via a Z' resonance.
We present various properties of the production of the X(3872) and ψ(2S) states based on 10.4 fb−1 collected by the D0 experiment in Tevatron pp collisions at √s = 1.96 TeV. For both states, we ...measure the nonprompt fraction fNP of the inclusive production rate due to decays of b-flavored hadrons. We find the fNP values systematically below those obtained at the LHC. The fNP fraction for ψ(2S) increases with transverse momentum, whereas for the X(3872) it is constant within large uncertainties, in agreement with the LHC results. The ratio of prompt to nonprompt ψ(2S) production, (1 − fNP)=fNP, decreases only slightly going from the Tevatron to the LHC, but for the X(3872), this ratio decreases by a factor of about 3. We test the soft-pion signature of the X(3872) modeled as a weakly bound charm-meson pair by studying the production of the X(3872) as a function of the kinetic energy of the X(3872) and the pion in the X(3872)π center-of-mass frame. For a subsample consistent with prompt production, the results are incompatible with a strong enhancement in the production of the X(3872) at the small kinetic energy of the X(3872) and the π in the X(3872)π center-of-mass frame expected for the X þ soft-pion production mechanism. For events consistent with being due to decays of b hadrons, there is no significant evidence for the soft-pion effect, but its presence at the level expected for the binding energy of 0.17 MeV and the momentum scale Λ ¼ M(π) is not ruled out.
Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in ...combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1-DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of
(AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound
is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
A CDK9 inhibitor having short target engagement would enable a reduction of Mcl-1 activity, resulting in apoptosis in cancer cells dependent on Mcl-1 for survival. We report the optimization of a ...series of amidopyridines (from compound 2), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound 24, a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2 and Mcl-1, resulting in cell apoptosis in multiple hematological cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound 24 is currently in clinical trials for the treatment of hematological malignancies.
Optimization of a series of azabenzimidazoles identified from screening hit 2 and the information gained from a co-crystal structure of the azabenzimidazole-based lead 6 bound to CDK9 led to the ...discovery of azaindoles as highly potent and selective CDK9 inhibitors. With the goal of discovering a highly selective and potent CDK9 inhibitor administrated intravenously that would enable transient target engagement of CDK9 for the treatment of hematological malignancies, further optimization focusing on physicochemical and pharmacokinetic properties led to azaindoles 38 and 39. These compounds are highly potent and selective CDK9 inhibitors having short half-lives in rodents, suitable physical properties for intravenous administration, and the potential to achieve profound but transient inhibition of CDK9 in vivo.
We extract the total width of the top quark, Γ(t), from the partial decay width Γ(t → Wb) measured using the t-channel cross section for single top-quark production and from the branching fraction ...B(t → Wb) measured in tt events using up to 2.3 fb(-1) of integrated luminosity collected by the D0 Collaboration at the Tevatron pp Collider. The result is Γ(t) = 1.99(-0.55)(+0.69) GeV, which translates to a top-quark lifetime of τ(t) = (3.3(-0.9)(+1.3)) × 10(-25) s. Assuming a high mass fourth generation b' quark and unitarity of the four-generation quark-mixing matrix, we set the first upper limit on |V(tb')| < 0.63 at 95% C.L.
We present a search for charged Higgs bosons in decays of top quarks, in the mass range $80 < m_{H^{\pm} < 155$ GeV, assuming the subsequent decay $H^{+} \to \tau^{+} \nu_\tau$ (and its charge ...conjugate). Using 0.9 fb$^{-1}$ of lepton+jets data collected with the D0 detector at the Fermilab Tevatron $p\bar{p}$ collider, operating at a center of mass energy $\sqrt{s}=1.96$ TeV, we find no evidence for a $H^{\pm}$ signal. Hence, we exclude branching ratios $B(t \to H^+b) > 0.24$ for $m_{H^{\pm}=80$ GeV, and $B(t \to H^+b) > 0.19$ for $m_{H^{\pm}=155$ GeV, at the 95% C.L.
Abstract
Purpose:
Targeting Bcl-2 family members upregulated in multiple cancers has emerged as an important area of cancer therapeutics. While venetoclax, a Bcl-2–selective inhibitor, has had ...success in the clinic, another family member, Bcl-xL, has also emerged as an important target and as a mechanism of resistance. Therefore, we developed a dual Bcl-2/Bcl-xL inhibitor that broadens the therapeutic activity while minimizing Bcl-xL–mediated thrombocytopenia.
Experimental Design:
We used structure-based chemistry to design a small-molecule inhibitor of Bcl-2 and Bcl-xL and assessed the activity against in vitro cell lines, patient samples, and in vivo models. We applied pharmacokinetic/pharmacodynamic (PK/PD) modeling to integrate our understanding of on-target activity of the dual inhibitor in tumors and platelets across dose levels and over time.
Results:
We discovered AZD4320, which has nanomolar affinity for Bcl-2 and Bcl-xL, and mechanistically drives cell death through the mitochondrial apoptotic pathway. AZD4320 demonstrates activity in both Bcl-2– and Bcl-xL–dependent hematologic cancer cell lines and enhanced activity in acute myeloid leukemia (AML) patient samples compared with the Bcl-2–selective agent venetoclax. A single intravenous bolus dose of AZD4320 induces tumor regression with transient thrombocytopenia, which recovers in less than a week, suggesting a clinical weekly schedule would enable targeting of Bcl-2/Bcl-xL–dependent tumors without incurring dose-limiting thrombocytopenia. AZD4320 demonstrates monotherapy activity in patient-derived AML and venetoclax-resistant xenograft models.
Conclusions:
AZD4320 is a potent molecule with manageable thrombocytopenia risk to explore the utility of a dual Bcl-2/Bcl-xL inhibitor across a broad range of tumor types with dysregulation of Bcl-2 prosurvival proteins.
We report on a search for charged massive long-lived particles (CMLLPs), based on 5.2 fb(-1) of integrated luminosity collected with the D0 detector at the Fermilab Tevatron pp collider. We search ...for events in which one or more particles are reconstructed as muons but have speed and ionization energy loss (dE/dx) inconsistent with muons produced in beam collisions. CMLLPs are predicted in several theories of physics beyond the standard model. We exclude pair-produced long-lived gauginolike charginos below 267 GeV and Higgsino-like charginos below 217 GeV at 95% C.L., as well as long-lived scalar top quarks with mass below 285 GeV.
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