2019
DOI: 10.1021/acs.jmedchem.8b01733
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Discovery of (R)-8-(6-Methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(1-methylcyclopropyl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one, a Potent and Selective Pim-1/2 Kinase Inhibitor for Hematological Malignancies

Abstract: Pim kinases are a family of constitutively active serine/threonine kinases that are partially redundant and regulate multiple pathways important for cell growth and survival. In human disease, high expression of the three Pim isoforms has been implicated in the progression of hematopoietic and solid tumor cancers, which suggests that Pim kinase inhibitors could provide patients with therapeutic benefit. Herein, we describe the structure-guided optimization of a series of quinazolinone-pyrrolodihydro­pyrrolone … Show more

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Cited by 22 publications
(13 citation statements)
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References 32 publications
(69 reference statements)
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“…The drug did exhibit in vitro off-target effects on PIM isoforms and DYRK3 (Fig. 3 D and E ), both of which have been reported to be potentially oncogenic (38, 39, 46). However, tumors derived from DYRK2 KO cells did not show a significant reduction upon LDN192960 treatment (Fig.…”
Section: Discussionmentioning
confidence: 92%
See 1 more Smart Citation
“…The drug did exhibit in vitro off-target effects on PIM isoforms and DYRK3 (Fig. 3 D and E ), both of which have been reported to be potentially oncogenic (38, 39, 46). However, tumors derived from DYRK2 KO cells did not show a significant reduction upon LDN192960 treatment (Fig.…”
Section: Discussionmentioning
confidence: 92%
“…We know from our previous studies that DYRK2 KO cells do not exhibit further reduction of proteasome activity upon treatment with DYRK2 inhibitor (19). However, we understand that LDN192960 also inhibits PIM kinases, which have been known to be targets in MM (38, 39); hence, we wanted to ascertain the relative contributions of DYRK2 versus other kinases toward the in vivo effects observed with LDN192960 treatment. We generated an s.c. xenograft model by injecting MM.1S cells (parental or DYRK2 KO) into nude J:NU mice and investigated whether LDN192960 treatment could further reduce MM tumors in the absence of DYRK2 (Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Electronic and conformational properties of the MCP group have received much less attention . However, this substituent is present in pharmaceuticals, biomimetics, and other practically important compounds, determining their properties. The additional methyl group makes the MCP fragment more donating and increases the rotation barrier.…”
Section: Resultsmentioning
confidence: 99%
“…LCMS (m/z): 556.4 [M + H] + . After partitioned between EtOAc (10 mL) and water (10 mL), the crude product was (20). To a solution of (±)-(1S,5S,6S)-6-bromo-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol 19 (1.05 g, 3.35 mmol) in THF (33.5 mL) was added potassium tert-butoxide (0.564 g, 5.03 mmol) at room temperature.…”
Section: ■ Experimental Sectionmentioning
confidence: 99%
“…In addition, elevated expression of PIM2 specifically has been described in multiple myeloma relative to other hematologic cancers, and this expression has been shown to be required for proliferation, presenting an effective pharmacological target for inhibition . However, identification of pan-PIM inhibitors retaining potent PIM2 inhibitory capacity in myeloma cells is challenging given the 10–100 times lower K m for ATP possessed by PIM2 relative to PIM1 and PIM3. …”
Section: Introductionmentioning
confidence: 99%