William T. McMillen's scientific contributionswhile working at Eli Lilly, Indianapolis, IN, United States and other institutions
- Abstract: Pyrazole-based inhibitors of the transforming growth factor-beta type I receptor kinase domain (TbetaR-I) are described. Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase. A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TbetaR-I receptor kinase domain.
- Abstract: We have expanded our previously reported series of pyrazole-based inhibitors of the TGF-beta type I receptor kinase domain (TbetaR-I) to now include new 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole analogues. Limited examination of the SAR of this new series in both enzyme and cell based in vitro assays has revealed selectivity differences with respect to p38 MAP kinase (p38 MAPK) depending on the nature of the 'warhead' group on the dihydropyrrolopyrazole ring. As with our original pyrazole... Show More
- Abstract: Transforming growth factor β (TGF-β) signaling pathways regulate a wide variety of cellular processes including cell proliferation, differentiation, extracellular matrix deposition, development, and apoptosis. TGF-β type-I receptor (TβRI) is the major receptor that triggers several signaling events by activating downstream targets such as the Smad proteins. The intracellular kinase domain of TβRI is essential for its function. In this study, we have identified a short phospho-Smad peptide,... Show More
- Abstract: Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-beta type I receptor (TGF-beta RI), TGF-beta RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-beta RI inhibitors and selective versus TGF-beta RII and MLK-7 kinases. Benzimidazole derivative 8b was active in an in vivo target (TGF-beta RI) inhibition assay.
- Abstract: A simple and efficient synthesis of dihydropyrrolopyrazole boronic acid intermediate (5) has been developed. Utilization of a three-component Suzuki–Miyaura/etherification with microwave heating led to advanced compound 11 in high yield and with easy purification. Reaction of compound 11 with methanesulfonyl chloride at room temperature furnished the 1,3 O–N rearranged product (12), which is postulated to proceed via an intramolecular mechanism. The outlined synthesis provides a highly... Show More
- Abstract: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
- Abstract: In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.
Publications citing this author (453)
[Show abstract] [Hide abstract] ABSTRACT: A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, well-established substrates of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFβ and the protein remained predominatly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.
- Structure-activity relationship analysis of new 4-methyl DPPs revealed that 2-(6-methylpyridin-2-yl) derivatives are clearly more potent than the corresponding 2-(6-ethylpyridin-2-yl) homologs (4S-4k > 4S-4l, 4R-4k > 4R-4l, 4d > 4g, 4e > 4h). Absence of the methyl at position 6 on 2-(pyridin-2-yl) ring however reduces the potency (4m is 8-fold less potent than 4o, 4n is 15-fold less potent than 4p); similar trend applies also to the recently described DPPs without any substitution at C4 [18,23,24]. Finally, we addressed the effect of the cyano group on the molecule.
[Show abstract] [Hide abstract] ABSTRACT: The effects of transforming growth factor beta (TGF-β) signaling on prostate tumorigenesis has been shown to be strongly dependent on the stage of development, with TGF-β functioning as a tumor suppressor in early stages of disease and as a promoter in later stages. To study in further detail the paradoxical tumor-suppressive and tumor-promoting roles of the TGF-β pathway, we investigated the effect of systemic treatment with a TGF-β inhibitor on early stages of prostate tumorigenesis. To ensure effective inhibition, we developed and employed a novel trivalent TGF-β receptor trap, RER, comprised of domains derived from the TGF-β type II and type III receptors. This trap was shown to completely block TβRII binding, to antagonize TGF-β1 and TGF-β3 signaling in cultured epithelial cells at low picomolar concentrations, and it showed equal or better anti-TGF-β activities than a pan TGF-β neutralizing antibody and a TGF-β receptor I kinase inhibitor in various prostate cancer cell lines. Systemic administration of RER inhibited prostate tumor cell proliferation as indicated by reduced Ki67 positive cells and invasion potential of tumor cells in high grade prostatic intraepithelial neoplasia (PIN) lesions in the prostate glands of Pten conditional null mice. These results provide evidence that TGF-β acts as a promoter rather than a suppressor in the relatively early stages of this spontaneous prostate tumorigenesis model. Thus, inhibition of TGF-β signaling in early stages of prostate cancer may be a novel therapeutic strategy to inhibit the progression as well as the metastatic potential in patients with prostate cancer.
- The TGF-β panneutralizing antibody 1D11 was purchased from BioXCell (BioXCell, West Lebanon, NH). HTS466284 (HTS), an ATP competitive inhibitor of TβRI kinase [47, 48], was synthesized by the Chemical Synthesis Core of Vanderbilt University.
[Show abstract] [Hide abstract] ABSTRACT: High-grade glioma (HGG), a deadly primary brain malignancy, manifests radioresistance mediated by cell-intrinsic and microenvironmental mechanisms. High levels of the cytokine transforming growth factor-β (TGF-β) in HGG promote radioresistance by enforcing an effective DNA damage response and supporting glioma stem cell self-renewal. Our analysis of HGG TCGA data and immunohistochemical staining of phosphorylated Smad2, which is the main transducer of canonical TGF-β signaling, indicated variable levels of TGF-β pathway activation across HGG tumors. These data suggest that evaluating the putative benefit of inhibiting TGF-β during radiotherapy requires personalized screening. Thus, we used explant cultures of seven HGG specimens as a rapid, patient-specific ex vivo platform to test the hypothesis that LY364947, a small molecule inhibitor of the TGF-β type I receptor, acts as a radiosensitizer in HGG. Immunofluorescence detection and image analysis of γ-H2AX foci, a marker of cellular recognition of radiation-induced DNA damage, and Sox2, a stem cell marker that increases post-radiation, indicated that LY364947 blocked these radiation responses in five of seven specimens. Collectively, our findings suggest that TGF-β signaling increases radioresistance in most, but not all, HGGs. We propose that short-term culture of HGG explants provides a flexible and rapid platform for screening context-dependent efficacy of radiosensitizing agents in patient-specific fashion. This time- and cost-effective approach could be used to personalize treatment plans in HGG patients.
- We assessed the TGF-β responsiveness and efficacy of inhibition by LY364947 (RIKI). In cell-free assays, LY364947 inhibits TGFβRI (ALK5) with an IC 50 of 0.58 μM , but nonspecific effects on other kinases have been demonstrated . RIKI has been used at concentrations ranging from 0.4 to 10 μM in cell-based assays [8,44,45].
[Show abstract] [Hide abstract] ABSTRACT: Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration.
- Both small molecule inhibitors of c-Myc and Fgf suppressed neuromast HC regeneration but have no effect on normal HCs (S7 Fig).As another control, we tested inhibition of the TGF-β1 pathway that did not show significant change in chick HC regeneration. Suppression of Tgf-β1 by an inhibitor ([3-(pyridin-2-yl)-4-(4-quinonyl]-1H-pyrazole)  over a range of concentrations did not significantly affect the number of HCs regenerated after neomycin treatment (S8 Fig),further supporting the pathway-specific inhibition of c-Myc and Fgf.
[Show abstract] [Hide abstract] ABSTRACT: New diarylquinazolines displaying pharmaceutical potential were synthesized in high yields from 4,7-dichloro-2-(2-methylprop-1-enyl)-6-nitroquinazoline by using microwave-promoted regioselective Suzuki-Miyaura cross-coupling reactions.
- In continuation of the recent Suzuki-Miyaura monocoupling reactions which we presented in the original 2-(2-methylprop-1-enyl)-6-nitroquinazoline series , we investigated the synthesis of a series of new biarylsubstituted-quinazolines, via a regioselective Suzuki-Miyaura cross coupling reaction. It was already known in literature [27,28] that the quinazoline C4 position is quite electrophilic. We therefore investigated the possibility of using 4,7-dichloro-2-(2-methylprop-1-enyl)- 6-nitroquinazoline (5) with various arylboronic acids, aiming at preparing dissymmetric biarylsubstituted quinazolines, taking into account that chlorinated aromatic carbon atoms, at position of a nitro group, also display a high reactivity when involved in palladium-catalyzed coupling reactions .
Indianapolis, IN, United States
- Lilly Research Laboratories