YAP1 INHIBITORS THAT TARGET THE INTERACTION OF YAP1 WITH OCT4Binding 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 cell lung 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.A compound having Formula IFormula Iwherein,X is C(O), S(O), or S02;Y is CH, CR6, or N;Z is CH2, CR6R7, or NH;R1 is Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, Ci-Cs alkoxyl, Ci-Cs heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=0), Ci-C6 alkyl, Ci-Ge haloalkyl, Ci-Ge alkoxyl, amino, -NR6R7, -C(0)NR6R7, Ci-Ce alkylhydroxy, C3-Ce cycloalkyl, C3-Ce heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;R2 is amino, hydroxyl, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, Ci-Cs alkoxyl, Ci-Cs heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=0), carboxyl (-CO2-), ester (CO2R6), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, amino, -NR6R7, - C(0)NR6R7, Ci-Ce alkylCs-ecycloalkyl, C3-Ce cycloalkyl, C3-Ce heterocycloalkyl, aryl, heteroaryl, Ci-6alkylaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;each R3 is, independently, hydrogen, halogen, OH, Ci-Cs alkyl, Ci-Cs alkoxyl, aryl, O- aryl, heteroaryl, O-heteroaryl, 0-CH2aryl, or 0-CH2heteroaryl; andR6 and R7 are independently selected from hydrogen, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, Ci-Cs alkoxide, Ci-Cs carboxylate, Ci-Cs haloalkyl, Ci-Cs haloalkenyl, Ci- C8 haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, C1-C3 alkylheteroaryl, or heteroaryl; any of which is optionally substituted with a halogen; and n is 1-5. 2. A compound having Formula II Formula IIwherein,R1 is hydrogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Ci-Ce alkoxyl, Ci-Ceheteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=0), Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-Ce alkoxyl, amino, -NR6R7, -C(0)NR6R7, Ci-Ce alkylhydroxy, C3-Ce cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;R2 is amino, hydroxyl, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Ci-Ce alkoxyl, Ci-Ce heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=0), carboxyl (-CO2-), ester (CO2R6), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, amino, -NR6R7, - C(0)NR6R7, Ci-Ce alkylCs-ecycloalkyl, C3-Ce cycloalkyl, C3-Ce heterocycloalkyl, aryl, heteroaryl, Ci-6alkylaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;each R3 is, independently, hydrogen, halogen, OH, Ci-Ce alkyl, Ci-Ce alkoxyl, aryl, O- aryl, heteroaryl, O-heteroaryl, 0-CH2aryl, or O-Grhheteroaryl; andR6 and R7 are independently selected from hydrogen, Ci-Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, Ci-Ce alkoxide, Ci-Ce carboxylate, Ci-Ce haloalkyl, Ci-Ce haloalkenyl, Ci- C8 haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, C1-C3 alkylheteroaryl, or heteroaryl; any of which is optionally substituted with a halogen; and n is 1-5. 3. A compound hFormula IIIwherein, X is C(O), S(O), or S02;Y is CH, CR6, or N;Z is CH2, CR6R7, or NH;W is cyano, C2-C4 alkyne, or a triazole, tetrazole or oxaxole optionally substituted with one or more carbonyl (C=0), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, - NR6R7, -C(0)NR6R7, Ci-Ce alkylhydroxy, C3-Ce cycloalkyl, C3-Ce heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;R1 is Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, Ci-Cs alkoxyl, Ci-Cs heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=0), Ci-C6 alkyl, Ci-C6 haloalkyl, Ci-C6 alkoxyl, amino, -NR6R7, -C(0)NR6R7, Ci-Ce alkylhydroxy, C3-Ce cycloalkyl, C3-Ce heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;R2 is amino, hydroxyl, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl, Ci-Cs alkoxyl, Ci-Cs heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=0), carboxyl (-CO2-), ester (CO2R6), Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxyl, amino, -NR6R7, - C(0)NR6R7, Ci-Ce alkylCs-ecycloalkyl, C3-Ce cycloalkyl, C3-Ce heterocycloalkyl, aryl, heteroaryl, Ci-6alkylaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;each R3 is, independently, hydrogen, halogen, OH, Ci-Cs alkyl, Ci-Cs alkoxyl, aryl, O- aryl, heteroaryl, O-heteroaryl, 0-CH2aryl, or 0-CH2heteroaryl; andR6 and R7 are independently selected from hydrogen, Ci-Cs alkyl, Ci-Cs alkenyl, Ci-Cs alkynyl,Ci-C8 alkoxide, Ci-Cs carboxylate, Ci-Cs haloalkyl, Ci-Cs haloalkenyl, Ci-Cs haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, C1-C3 alkylheteroaryl, or heteroaryl; any of which is optionally substituted with a halogen; and n is 1 -5.
YAP1과 OCT4의 상호작용을 표적으로 하는 YAP1 저해제전사 인자 Oct4에 대한 전사 공활성인자인 YAP1의 결합은 Sox2를 유도하는데, 이것은 비소세포 폐암으로부터의 줄기-유사 세포의 자가 재생에 필수적인 전사 작용인자이다. YAP1의 WW 도메인은 Oct4의 PPxY 모티프에 결합하여 Sox2를 유도한다. WW 도메인에 상응하는 펩타이드를 전달하는 것을 Sox2의 유도 및 줄기능을 예방할 수 있다. 유사하게, PPxY 모티프의 펩타이드 및 모방체는 줄기능을 저해할 수 있을 것이다. Yap1:Oct4 상호작용에 영향을 미치는 화합물이 개시된다.하기 화학식 I을 갖는 화합물: 화학식 I상기 식 중,X는 C(O), S(O) 또는 SO2이고; Y는 CH, CR6 또는 N이며; Z는 CH2, CR6R7 또는 NH이고; R1은 C1-C8 알킬, C1-C8 알켄일, C1-C8 알킨일, C1-C8 알콕실, C1-C8 헤테로알킬, C3-C6 사이클로알킬, C3-C6 헤테로사이클로알킬, 아릴 또는 헤테로아릴이고, 이들 중 임의의 것은 하나 이상의 카보닐(C=O), C1-C6 알킬, C1-C6 할로알킬, C1-C6 알콕실, 아미노, -NR6R7, -C(O)NR6R7, C1-C6 알킬하이드록시, C3-C6 사이클로알킬, C3-C6 헤테로사이클로알킬, 아릴, 헤테로아릴, 할로, 하이드록실, 티올, 사이아노, 나이트로 또는 방사성 표지된 동위원소로 임의로 치환되며; R2는 아미노, 하이드록실, C1-C8 알킬, C1-C8 알켄일, C1-C8 알킨일, C1-C8 알콕실, C1-C8 헤테로알킬, C3-C6 사이클로알킬, C3-C6 헤테로사이클로알킬, 아릴 또는 헤테로아릴이고, 이들 중 임의의 것은 하나 이상의 카보닐(C=O), 카복실(-CO2-), 에스터(CO2R6), C1-C6 알킬, C1-C6 할로알킬, C1-C6 알콕실, 아미노, -NR6R7, -C(O)NR6R7, C1-C6 알킬C3-6사이클로알킬, C3-C6 사이클로알킬, C3-C6 헤테로사이클로알킬, 아릴, 헤테로아릴, C1-6알킬아릴, 할로, 하이드록실, 티올, 사이아노, 나이트로 또는 방사성 표지된 동위원소로 임의로 치환되고; 각각의 R3은, 독립적으로, 수소, 할로겐, OH, C1-C8 알킬, C1-C8 알콕실, 아릴, O-아릴, 헤테로아릴, O-헤테로아릴, O-CH2아릴 또는 O-CH2헤테로아릴이며;R6 및 R7은 수소, C1-C8 알킬, C1-C8 알켄일, C1-C8 알킨일, C1-C8 알콕사이드, C1-C8 카복실레이트, C1-C8 할로알킬, C1-C8 할로알켄일, C1-C8 할로알킨일, C3-C6 사이클로알킬, C3-C6 헤테로사이클로알킬, 아릴, C1-C3 알킬헤테로아릴 또는 헤테로아릴로부터 독립적으로 선택되고; 이들 중 임의의 것은 할로겐으로 임의로 치환되고; n은 1 내지 5이다.