An open-label, dose-escalation study to assess safety, pharmacokinetics and efficacy as well as determine the recommended Phase 2 doses of co-administered therapy of dinaciclib and venetoclax for patients with relapsed or refractory Acute Myeloid Leukemia (R/R AML).

Start Date23 Jul 2018

Sponsor / Collaborator

AbbVie, Inc.

[+1]

NCT01676753 / CompletedPhase 1IIT

A Phase 1b Trial of the Cyclin-dependent Kinase Inhibitor Dinaciclib in Combination With Pembrolizumab in Patients With Advanced Breast Cancer and Assessment of MYC Oncogene Overexpression

The purpose of this trial is to determine the safety and tolerability (maximum tolerated dose (MTD)) of weekly dinaciclib in combination with pembrolizumab in patients with advanced breast cancer. Once this is defined, dose expansion will be performed at this MTD in patients with metastatic or locally advanced and unresectable triple negative breast cancer, to evaluate the efficacy of combined dinaciclib and pembrolizumab.

Start Date28 Dec 2016

Sponsor / Collaborator

The University of California, San Francisco

[+1]

100 Clinical Results associated with CDK5 x CDK2 x CDK1 x CDK9

100 Translational Medicine associated with CDK5 x CDK2 x CDK1 x CDK9

0 Patents (Medical) associated with CDK5 x CDK2 x CDK1 x CDK9

Literatures (Medical) associated with CDK5 x CDK2 x CDK1 x CDK9

01 Dec 2024·Bioorganic Chemistry

Heterocycle-functional steroidal derivatives: Design, synthesis, bioevaluation and SARs of steroidal pyrazolo[1,5-a]pyrimidines as potential ALK inhibitors

Article

Author: Ke, Shaoyong ; Yang, Fei ; Min, Yong ; Liu, Manli ; Yang, Ziwen ; Shi, Liqiao ; Deng, Yunxia ; Wen, Shaohua ; Zhang, Zhigang ; Wang, Kaimei ; Liu, Fang

Two series of heterocyclic steroidal pyrazolo[1,5-a]pyrimidines derived from dehydroepiandrosterone (DHEA) and epiandrosterone (EPIA) were designed and synthesized, and these compounds were screened for their potential antiproliferation activities. The preliminary bioassay indicated that some of target compounds exhibited significantly good antiproliferation activities against human melanoma cell line (A875) and human hepatocellular carcinoma (Huh-7) cell lines compared with 5-fluorouracil (5-FU), and some of which present good antiproliferative activities as potential ALK inhibitors. The detailed analysis of structure-activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5-a]pyrimidine might be affected by the β-hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, CDK9/CyclinT1, CDK5/P25, PIM2, CDK2/CyclinA2, CDK1/CyclinB1, etc., and which displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63 % at the concentration of 10 μM, which induced cell death in A875 cells at least partly (initially), by apoptosis.

01 Oct 2023·Investigational new drugs

Development of novel palbociclib-based CDK4/6 inhibitors exploring the back pocket behind the gatekeeper.

Article

Author: Li, Lina ; Xue, Xia ; Chen, Fengquan ; Liao, Yongxiang ; Li, Mengzhe ; Luan, Yun ; Wang, Yongjie ; Jiang, Wen

CDK4/6 inhibitors plus endocrine therapy is a standard therapy for HR+/HER2- breast cancer. Herein, using structure-based drug design strategy, a novel series of palbociclib derivatives were designed and synthesized as CDK4/6 inhibitors, among which compound 17m exhibited more potent CDK4/6 inhibitory activity and in vitro antiproliferative activity against the phosphorylated Rb-positive cell line MDA-MB-453 than the approved drug palbociclib. Moreover, compound 17m possessed remarkable CDK4/6 selectivity over other CDK family members including CDK1, CDK2, CDK3, CDK5, CDK7 and CDK9. The potent and selective CDK4/6 inhibitory activity endowed compound 17m with robust G1 cell cycle arrest ability in MDA-MB-453 cells. The intracellular inhibition of CDK4/6 by 17m was confirmed by western blot analysis of the levels of phosphorylated Rb in MDA-MB-453 cells. With respect to the metabolic stability, compound 17m possessed longer half-life (t_1/2) in mouse liver microsome than palbociclib.

01 Dec 2021·Bioorganic Chemistry

Synthesis of a new series of pyrazolo[1,5-a]pyrimidines as CDK2 inhibitors and anti-leukemia

Article

Author: Farghaly, Thoraya A ; Almehmadi, Samar J ; Alsaedi, Amani M R ; Harras, Marwa F

Based on the structural study of previously known CDK2 inhibitors, a new series of pyrazolo[1,5-a]pyrimidine derivatives was designed and synthesized. The target compounds were biologically assessed as potent CDK2 inhibitors and promising anti-leukemia hits. The 7-(4-Bromo-phenyl)-3-(3-chloro/2-chloro-phenylazo)-pyrazolo[1,5-a]pyrimidin-2-ylamines 5 h and 5i revealed the best CDK2 inhibitory activity with comparable potency (IC₅₀ = 22 and 24 nM, respectively) to that of dinaciclib (IC₅₀ = 18 nM). Additionally, both analogues showed potent activities against CDK1, CDK5 and CDK9 at nanomolar concentrations (IC₅₀ = 28-80 nM). The anti-leukemia screening of the target compounds showed strong to moderate cytotoxicity against the used leukemia cell lines (MOLT-4 and HL-60). Compound 5 h inhibited MOLT-4 and HL-60 by 1.4 and 2.3 folds (IC₅₀ = 0.93 and 0.80 µM), respectively, compared to dinaciclib (IC₅₀ = 1.30 and 1.84 µM). Furthermore, compound 5i was comparable to dinaciclib against MOLT-4 and exhibited twice its activity against HL-60. Besides, the cytotoxicity of the promising analogues on normal human blood cells indicated the safety of 5h and 5i as compared to the reference dinaciclib. The pharmacokinetic properties of 5h and 5i were predicted using ADME calculations revealing good oral bioavailability and high GI absorption. The molecular docking simulations indicated, as expected, that the dinaciclib analogues can well-accommodate the CDK2 binding site, forming a variety of interactions.

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