Discovery of (4-Pyrazolyl)-2-aminopyrimidines as Potent and Selective Inhibitors of Cyclin-Dependent Kinase 2.

CDK2 is a critical regulator of the cell cycle. For a variety of human cancers, the dysregulation of CDK2/cyclin E1 can lead to tumor growth and proliferation. Historically, early efforts to develop CDK2 inhibitors with clinical applications proved unsuccessful due to challenges in achieving selectivity over off-target CDK isoforms with associated toxicity.

Discovery of 5,7-Dihydro-6-pyrrolo[2,3-]pyrimidin-6-ones as Highly Selective CDK2 Inhibitors.

A series of exceptionally selective CDK2 inhibitors are described. Starting from an HTS hit, we successfully scaffold hopped to a 5,7-dihydro-6-pyrrolo[2,3-]pyrimidin-6-one core structure, which imparted a promising initial selectivity within the CDK family. Extensive further SAR identified additional factors that drove selectivity to above 200× for CDKs 1/4/6/7/9.

Discovery of Novel Pyrazolopyrimidines as Potent, Selective, and Orally Bioavailable Inhibitors of ALK2.

Activin receptor-like kinase 2 (ALK2) is a transmembrane kinase receptor that mediates the signaling of the members of the TGF-β superfamily. The aberrant activation of ALK2 has been linked to the rare genetic disorder fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) that are associated with severely reduced life expectancy in pediatric patients. ALK2 has also been shown to play an essential role in iron metabolism by regulating hepcidin levels and affecting anemia of chronic disease.

Inhibition of ALK2 with bicyclic pyridyllactams.

Activin receptor-like kinase 2 (ALK2) has been implicated as a key target in multiple rare diseases. Herein, we describe the design of a novel bicyclic lactam series of potent and selective ALK2 inhibitors. This manuscript details an improvement in potency of two orders of magnitude from the initial bicyclic structure as well as a two-fold improvement in cellular potency from the original monocyclic inhibitor.

Discovery of Pemigatinib: A Potent and Selective Fibroblast Growth Factor Receptor (FGFR) Inhibitor.

Aberrant activation of FGFR has been linked to the pathogenesis of many tumor types. Selective inhibition of FGFR has emerged as a promising approach for cancer treatment. Herein, we describe the discovery of compound (INCB054828, pemigatinib), a highly potent and selective inhibitor of FGFR1, FGFR2, and FGFR3 with excellent physiochemical properties and pharmacokinetic profiles.

INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models.

Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials.

Rosamines targeting the cancer oxidative phosphorylation pathway.

Reprogramming of energy metabolism is pivotal to cancer, so mitochondria are potential targets for anticancer therapy. A prior study has demonstrated the anti-proliferative activity of a new class of mitochondria-targeting rosamines. This present study describes in vitro cytotoxicity of second-generation rosamine analogs, their mode of action, and their in vivo efficacies in a tumor allografted mouse model.

High-contrast fluorescence imaging in fixed and living cells using optimized optical switches.

We present the design, synthesis and characterization of new functionalized fluorescent optical switches for rapid, all-visible light-mediated manipulation of fluorescence signals from labelled structures within living cells, and as probes for high-contrast optical lock-in detection (OLID) imaging microscopy. A triazole-substituted BIPS (TzBIPS) is identified from a rational synthetic design strategy that undergoes robust, rapid and reversible, visible light-driven transitions between a colorless spiro- (SP) and a far-red absorbing merocyanine (MC) state within living cells. The excited MC-state of TzBIPS may also decay to the MC-ground state emitting near infra-red fluorescence, which is used as a sensitive and quantitative read-out of the state of the optical switch in living cells.

Energy transfer cassettes in silica nanoparticles target intracellular organelles.

Lipophilic energy transfer cassettes like 1 and 2 are more conveniently synthesized than the corresponding hydrophilic compounds, but they are not easily used in aqueous media. To overcome the latter issue, cassettes 1 and 2 were separately encapsulated in silica nanoparticles (ca. 22 nm) which freely disperse in aqueous media.

Optical control of calcium affinity in a spiroamido-rhodamine based calcium chelator.

An optically controlled Ca(2+)-chelator 1 was developed to mimic natural calcium oscillations. Compound 1, a spiroamido-rhodamine derivative of 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), underwent cycles of reversible transitions between a colorless closed state and a fluorescent open form. The closed-state exhibited a high affinity for Ca(2+) (K(d): 509 nM) with excellent selectivity over Mg(2+) (K(d): 19 mM).

Organelle-selective energy transfer: a fluorescent indicator of intracellular environment.

A dye cassette fluoresces green (ca 520 nm) in the cytoplasm, endoplasmic reticulum (ER), and lysosomes, but red in mitochondria, that is, it illustrates 'organelle specific energy transfer'. This phenomenon may open new horizons in intracellular imaging.

Fluorescent cassettes for monitoring three-component interactions in vitro and in living cells.

Two water-soluble "through-bond energy transfer cassettes" (TBET-cassettes) were prepared. They have good extinction coefficients at the donor part and transfer energy to the acceptor parts with good "overall quantum yields" (0.30 and 0.

Functionalized BF(2) Chelated Azadipyrromethene Dyes.

Fluorescent molecules that emit in the near infra-red are potentially useful as probes for biotechnology. A relatively under-explored design for probes of this type are the aza-BODIPY dyes; this study was performed to enhance our understanding of these materials and ways in which they may be used in dye cassette systems. Thus, the aza-BODIPY dyes 1a - g were prepared.

New cytotoxic rosamine derivatives selectively accumulate in the mitochondria of cancer cells.

Conventional cytotoxic anticancer drugs that target all rapidly dividing cells are nonselective in their mechanism of action, because they disrupt essential components that are crucial to both malignant and proliferating normal cells. Instead, targeting cellular functions that are distinctly different between normal and cancer cells may provide a basis for selective killing of tumor cells. One such strategy that is still largely unexplored is to utilize the relatively higher negative mitochondrial membrane potential in carcinoma cells compared with adjacent normal epithelial cells to enhance accumulation and retention of cytotoxic lipophilic cations in the former.

A new synthesis of symmetric boraindacene (BODIPY) dyes.

BODIPY dyes were synthesized from pyrrole-2-carbaldehyde derivatives in high yields; this constitutes a new approach to this dye framework.

Synthesis and spectroscopic properties of rosamines with cyclic amine substituents.

There is a close structural similarity between rosamines A and rhodamines B, yet a diversity of structures in the rosamine class and their spectral properties have yet to be explored in depth. This manuscript describes a concise, scalable, solution-phase method to obtain rosamines 1-5 and 12-15, which include some water-soluble derivatives. In one test case (for 15) an illustrative protein conjugate was also formed.

Fluorescent amino- and thiopyronin dyes.

Highly fluorescent rhodamine/rosamine analogues 2 were prepared from ketone 1.

Syntheses of highly fluorescent GFP-chromophore analogues.

Eight B-containing compounds, i.e., 1a-h, were prepared as mimics of the green fluorescent protein (GFP) fluorophore.

Degradation of calcium lignosulfonate using gamma-ray irradiation.

Gamma-ray irradiation was proven to be a promising means for the removal of calcium lignosulfonate (CaLS). At a dose rate of 55Gy min(-1), over 90% of CaLS was mineralized to CO(2), H(2)O and sulfates within 3-d irradiation. The degradation of CaLS with the initial CaLS concentrations ranging from 40 to 200mg l(-1) followed zero-order kinetics at the dose rates of 16-150Gy min(-1).