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Yap1 inhibitors that target the interaction of yap1 with oct4

A C1-C6, C1-C8 technology, applied in the field of cancer treatment and anti-cancer compounds, YAP1 inhibitors, can solve problems such as low overall survival rate

Pending Publication Date: 2020-11-24
H LEE MOFFITT CANCER CENT & RES INST INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although chemotherapeutic agents such as gemcitabine, platinum compounds, and taxanes have improved survival to a limited extent, overall survival remains poor due to recurrence of more aggressive, drug-resistant tumors (Seve P et al, Non-Small Chemoresistance in Cellular Lung Cancer

Method used

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  • Yap1 inhibitors that target the interaction of yap1 with oct4
  • Yap1 inhibitors that target the interaction of yap1 with oct4
  • Yap1 inhibitors that target the interaction of yap1 with oct4

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] Example 1. (S)-3-cyclohexyl-2-(2-(1-(3-(3,4-dichlorophenyl)propionyl)piperidin-4-yl)acetamido)propionic acid Methyl ester (SR3-137).

[0148] Using the general method, (S)-methyl 2-amino-3-cyclohexylpropanoate hydrochloride (0.019 g, 0.087 mmol) gave SR3-137 as a white foam (0.036 g, 95%). HPLC: >98%[t R = 5.0 min, 75% MeOH, 25% water (with 0.1% TFA), 20 min]. 1 H NMR (500MHz, DMSO-d 6 )δ8.18(d, J=7.9Hz, 1H), 7.54(bs, 1H), 7.52(d, J=8.2Hz, 1H), 7.25(dd, J=8.3, 2.1Hz, 1H), 4.37– 4.27(m,2H),3.89–3.77(m,1H),3.63–3.57(m,3H),3.03–2.83(m,2H),2.81(t,J=7.6Hz,2H),2.68–2.57( m,2H),2.05(d,J=7.1Hz,2H),1.94–1.82(m,1H),1.72–1.56(m,8H),1.55–1.44(m,2H),1.39–1.22(m, 2H), 1.22–1.05(m,3H), 1.04–0.76(m,4H). HRMS (ESI+): C 26 h 37 Cl 2 N 2 o 4 (M+H) + The calculated value of m / z is 511.2125, and the measured value is 511.2142; C 26 h 36 Cl 2 N 2 o 4 Na(M+Na) + m / z calculated value 533.1944, found value 533.1951; HPLC-MS (ESI+): m / z 533.2 [100%, (M+Na) + ].

[0149]

Embodiment 2

[0150] Example 2. (S)-4-methyl-2-(2-(1-(3-(3,4-dichlorophenyl)propionyl)piperidin-4-yl)acetamido)pentanoic acid Methyl ester (SR3-139).

[0151] Using the general method, SR3-139 was obtained from L-leucine methyl ester hydrochloride (0.016 g, 0.087 mmol) as a white foam (0.032 g, 94%). HPLC: >96%[t R = 5.2 min, 70% MeOH, 30% water (with 0.1% TFA), 20 min]. 1 H NMR (500MHz, DMSO-d 6 )δ8.18(d, J=7.6Hz, 1H), 7.54(d, J=2.1Hz, 1H), 7.52(d, J=8.2Hz, 1H), 7.25(dd, J=8.2, 2.1Hz, 1H),4.40–4.18(m,2H),3.84(m,1H),3.61(s,3H),3.02–2.88(m,1H),2.88–2.73(m,2H),2.68–2.58(m, 2H),2.56(m,1H),2.05(d,J=7.3Hz,2H),1.96–1.80(m,1H),1.69–1.50(m,4H),1.51–1.38(m,1H),1.09 -0.92 (m, 2H), 0.89 (d, J=6.6Hz, 3H), 0.84 (d, J=6.5Hz, 3H). HRMS (ESI+): C 23 h 33 Cl 2 N 2 o 4 (M+H) + The m / z calculated value of 471.1812, the measured value of 471.1826; C 23 h 32 Cl 2 N 2 o 4 Na(M+Na) + m / z calculated value 493.1631, found value 493.1646; HPLC-MS (ESI+): m / z 471.3 [80%, (M+H) + ], m / z 493.2 [100%...

Embodiment 3

[0153] Example 3. (S)-2-(2-(1-(3-(3,4-dichlorophenyl)propionyl)piperidin-4-yl)acetamido)-3-(4-fluoro Methyl phenyl)propionate (SR3-174).

[0154] SR3-174 was obtained as a white foam (0.034 g, 89 %). HPLC: >99%[t R = 5.1 min, 70% MeOH, 30% water (with 0.1% TFA), 20 min]. 1 H NMR (500MHz, DMSO-d 6 )δ8.27(d,J=8.0Hz,1H),7.53(bs,1H),7.51(m,1H),7.25(m,2H),7.10(dd,J=8.8,1.8Hz,2H), 4.50(m,1H),4.26(m,1H),3.76(m,1H),3.61(s,3H),3.04(dd,J=13.8,5.2Hz,1H),2.91–2.75(m,4H) ,2.61(m,2H),2.48–2.36(m,1H),1.97(d,J=7.2Hz,2H),1.75(m,1H),1.48(m,1H),1.35(m,1H), 0.99–0.70 (m,2H). HRMS (ESI+): C 26 h 30 Cl 2 FN 2 o 4 (M+H) + The calculated value of m / z is 523.1561, and the measured value is 523.1584; C 26 h 29 Cl 2 FN 2 o 4 Na(M+Na) + m / z calculated value 545.1381, found value 545.1493; HPLC-MS (ESI+): m / z 545.2 [100%, (M+Na) + ].

[0155]

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PUM

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Abstract

Binding of the transcriptional co-activator, YAP1, to the transcription factor Oct4, induces Sox2, which is a transcription actor necessary for the self-renewal of stem-like cells from non-small celllung cancer. The WW domain of YAP1 binds to the PPxY motif of Oct4 to induce Sox2. Delivering a peptide corresponding to the WW domain could prevent the induction of Sox2 and stemness. Similarly, peptides and mimetics of the PPxY motif would be able to inhibit stemness. Disclosed are compounds that affect the Yap1:Oct4 interaction.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to US Provisional Application 62 / 643,032, filed March 14, 2018, which is incorporated herein by reference in its entirety. Background technique [0003] Lung cancer is the leading cause of cancer-related mortality in the United States (Siegel R et al., Cancer Statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30), most of which (85%) are caused by non-small caused by NSCLC. Patients with early disease are treated surgically, but approximately 30-60% develop recurrent tumors leading to death (Demicheli R et al., Relapse dynamics independent of recurrence site. Breast Cancer Res. 2008;10(5):R83; Demicheli R et al. Recurrence dynamics in non-small cell lung cancer: impact of surgery on metastatic development. J Thorac Oncol. 2012;7(4):723-30; Senthi S et al. After stereotaxic ablative radiation therapy for early-stage non-small cell lung cancer Patterns of disease recurrence:...

Claims

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Application Information

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IPC IPC(8): A61K31/454A61K31/496C07D401/06
CPCC07D401/06A61P35/00C07D211/34C07D401/10C07D401/12A61K31/445A61K31/454A61K31/4545A61K31/506A61K45/06
Inventor 斯里库玛·希尔拉潘尼古拉斯·J·劳伦斯苏吉瓦·拉纳通加·马汉泽·穆迪扬塞拉格
Owner H LEE MOFFITT CANCER CENT & RES INST INC
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