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US 2026/0199367 A1Published application
Plk1 degradation inducing compounds with increased rigidity
AssigneeUppthera, Inc.
InventorsSoo Hee Ryu, Seong Hoon Kim, Jun Kyu Lee, Keum Young Kang, Gibbeum Lee, Sang Youn Kim, Solhee Noh
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Abstract
Novel dihydropteridone or pyrimidodiazepinone derivative based PLK1 degraders are disclosed. The present PLK1 degraders are proteolysis targeting chimeras (PROTACs) that recruit PLK1 protein into CRBN E3 ubiquitin ligase via optimized rigid linkers. The compounds may induce PLK1 degradation with improved drug properties and may be utilized for example, as a payload of antibody-drug conjugated (ADC) for the treatment of cancer.
Claims13
A compound represented by the following Formula I:
- wherein:
- L1 is a covalent bond or —(X5)1-3— wherein X5 is each independently —CH2— or —NH— provided that —NH— is absent or present once at most in L1;
- L2 is a covalent bond or —(X6)1-3— wherein X6 is each independently —CH2—, —C(O)—, —NH— or —CH(NH2)— provided that —C(O)—, —NH—, —N(CH3)— and —CH(NH2) are each independently absent or present once at most in L2;
- L3 is
- wherein L3 is covalently bonded into X4 through ;
- X1, X2, X3 and X4 are each independently CH or N;
- X7 and X8a are each independently a covalent bond or —CH2—;
- X8b is —H or —CH3;
- and
- R1 is —OCH3 or —OCF3;
- wherein ULM is a moiety represented by the following Formula II-1, II-2 or II-3:
- wherein:
- Ring U is phenyl or 5- or 6-membered heteroaryl;
- U1 is —NH—, —NHCH2—, —NHCH2CH2—, —CH2NH—, —CH2CH2NH—, —NHCO—, —CONH— or —O—;
- U2 is CH2 or C(O);
- and
- RU is halo.
14 more elements
A compound represented by the following Formula III:
- wherein:
- L2 is —CH2—, —NHCH2—, —CH2NH—, —CH(NH2)CH2—, —CH2CH(NH2)—, —C(O)CH2CH2— or —CH2CH2C(O)—;
- X1, X2, X3 and X4 are each independently CH or N;
- X7 is a covalent bond or —CH2—;
- R2a and R2b are -halo, or R2a and R2b are linked each other to form 3- to 6-membered ring;
- and
- R3 is —C1-3alkyl or 3- to 7-membered cycloalkyl;
- wherein ULM is a moiety represented by the following Formula II-4:
- wherein U3 is a covalent bond or —NH—;
- and RU is halo.
7 more elements
Dependencies are inferred from the claim text.