ORCID Profile
0000-0002-5454-8958
Current Organisations
Research Centre of Medical Genetics
,
University of South Australia
,
University of Copenhagen Biotech Research and Innovation Centre
,
Københavns Universitet
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Publications
Potent and orally bioavailable CDK8 inhibitors: design, synthesis, structure-activity relationship analysis and biological evaluation
Publisher: Elsevier BV
Date: 03-2021
Epigenetic and Transcriptomic Characterization of Pure Adipocyte Fractions From Obese Pigs Identifies Candidate Pathways Controlling Metabolism
Publisher: Frontiers Media SA
Date: 17-12-2019
Abstract 2353: CDKI-15, a novel and highly selective CDK4/6 inhibitor: discovery, in vitro and in vivo anticancer efficacy
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2018
DOI: 10.1158/1538-7445.AM2017-2353
Abstract: Cyclin D dependent kinases CDK4 & CDK6 are crucial regulators of the G1 to S phase transition of the cell cycle. The facts that myriad cancer types show aberrance in INK4-CDK4/6-cyclin D-Rb-E2F pathway, & the rapidly emerging positive clinical data of pharmacological inhibitors have validated CDK4/6 as anticancer drug targets. As the first commercialized CDK inhibitor, palbociclib in combination with letrozole or fulvestrant has received regulatory approval for the treatment of breast cancer. This represents an important scientific advance in the field. However, the limited structural ersity & undesired side effects due to broader kinase interactions of existing inhibitors mean that the hunt for new & highly selective CDK4/6 inhibitor drug candidates continues. Using our advanced medicinal chemistry, targeted biochemical & cell-based assays, & animal pharmacology, we synthesized & evaluated a novel series of inhibitors. Many compounds were highly potent & selective against CDK4/6, & exhibited low nanomolar potency against a range of human cancer cell lines. Notably, inhibition of CDK4D1 by compound CDKI-15 (Ki = 4 nM) was over 3 orders of magnitude greater than CDK1B, CDK2A, CDK7H & CDK9T1. Interrogation of a panel of 369 protein kinases revealed CDKI-15 to be highly selective for CDK4/6 with only 3 other kinases inhibited potently. CDKI-15 reduced the level of Rb phosphorylation & induced G1 cell cycle arrest, confirming cellular inhibition of CDK4/6 in cancer cells. Moreover, CDKI-15 possesses superior pharmacokinetic profile with oral bioavailability of 100% in mice. Treatment of nude BALB/c mice bearing human MV4-11 acute myeloid leukemia cells with CDKI-15 at daily dose of 100 mg/kg by oral administration resulted in a robust inhibition of tumor growth compared to vehicle treated animals (T/C = 30%, p & 0.00001). Strikingly, CDKI-15 caused a complete & sustained tumor regression in one-third of the animals. No detectable toxicity was observed in the animals during & post treatment. Taken together, our data provide a rationale for CDKI-15 to be developed towards clinic for cancer therapy. Citation Format: Solomon Tadesse, Laychiluh Bantie, Khamis Tomusange, Saiful Islam, Muhammed H. Rahaman, Benjamin Noll, Frankie Lam, Mingfeng Yu, Shudong Wang. CDKI-15, a novel and highly selective CDK4/6 inhibitor: discovery, in vitro and in vivo anticancer efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr 2353. doi:10.1158/1538-7445.AM2017-2353
Anti-Leukaemic Activity of Rilpivirine Is Mediated by Aurora A Kinase Inhibition
Publisher: MDPI AG
Date: 07-02-2023
Abstract: Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell- ision cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes. In a previous study, we demonstrated that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In the current study, we have further explored the selectivity of rilpivirine for Aurora A kinase inhibition by testing this drug against a panel of 429 kinases. Concurrently, we demonstrated that rilpivirine significantly inhibited the proliferation of AML cells in a time- and concentration-dependent manner that was preceded by G2/M cell-cycle arrest leading to the induction of apoptosis. Consistent with its kinase inhibitory role, rilpivirine modulated the expression of critical proteins in the Aurora A kinase-signalling pathway. Importantly, orally administered rilpivirine significantly inhibited tumour growth in an HL-60 xenograft model without showing body weight changes or other clinical signs of toxicity. Furthermore, rilpivirine enhanced the anti-proliferative efficacy of the conventional anti-leukaemic chemotherapeutic agent cytarabine. Collectively, these findings provide the stimulus to explore further the anti-leukaemic activity of the anti-viral drug rilpivirine.
CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia
Publisher: Springer Science and Business Media LLC
Date: 08-09-2019
DOI: 10.1007/S10637-018-0661-2
Abstract: Acute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL) and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in the MLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and s les derived from 97 patients. CDKI-73 induced cancer cells undergoing apoptosis through transcriptional downregulation of anti-apoptotic proteins Bcl-2, Mcl-1 and XIAP by majorly targeting CDK9. Contrastively, it was relatively low toxic to the bone marrow cells of healthy donors. In MV4-11 xenograft mouse models, oral administration of CDKI-73 resulted in a marked inhibition of tumor growth (p < 0.0001) and prolongation of animal life span (P < 0.001) without causing body weight loss and other overt toxicities. The study suggests that CDKI-73 can be developed as a highly efficacious and orally deliverable therapeutic agent for treatment of AML.
Analysis of discordant Affymetrix probesets casts serious doubt on idea of microarray data reutilization
Publisher: Springer Science and Business Media LLC
Date: 12-2014
Abstract 4427: LS007, a potent and orally bioavailable CDK9 inhibitor, suppresses the growth of triple-negative and estrogen receptor-positive breast cancer
Publisher: American Association for Cancer Research (AACR)
Date: 07-2019
DOI: 10.1158/1538-7445.AM2019-4427
Abstract: Treatment of breast cancer represents a major therapeutic challenge, and thus identification of new targeted therapy is of paramount importance. Anti-apoptotic proteins, BCL2 and MCL1, and oncoprotein c-MYC are implicated in evasion of apoptosis and resistance to chemotherapy in both triple-negative breast cancer (TNBC) and estrogen receptor-positive breast cancer (ER+ BC). Transcription of these oncogenic factors requires cyclin dependent kinase 9 (CDK9). CDK9 phosphorylates the C-terminal domain (CTD) of RNA polymerase II (RNAPII) and acts as a rate-limiting step of transcription. Thus, targeting CDK9 can reduce the expression of these proteins effectively and simultaneously, presenting a promising therapeutic strategy for breast cancer. Utilizing extensive medicinal chemistry and biochemical assays, we previously identified and developed LS007 as an orally bioavailable (F = 56% in cynomolgus monkey at 4 mg/kg), and nanomolar inhibitor of CDK9 (Ki = 4 nM). In vitro, inhibition of CDK9-mediated phosphorylation of RNAPII (pRNAPIIS2) by LS007 resulted in downregulation of BCL2, MCL1 and c-MYC and activation of PARP cleavage indicating apoptosis in breast cancer cells (TNBC: MDA-MB-231, Hs578T and ER+ BC: MCF-7, T47D). In vivo, LS007 was well tolerated in mice after oral administration (MTD = 50 mg/kg QD and 100 mg/kg Q3D). In MDA-MB-231 TNBC xenograft, by daily oral dosing at 25 mg/kg and 50 mg/kg LS007 significantly reduced tumor growth (p & 0.001) with T/C of 53 % and 35 %, respectively, on day 21, when compared to the vehicle dosed group. Similarly, in MCF-7 ER+ BC xenograft model, oral dosing of LS007 at 25 mg/kg QD, 50 mg/kg Q2D and 75 mg/kg Q3D showed significant tumor growth inhibition with T/C of 50 %, 60 % and 47 %, respectively, and increased in animal survival (p & 0.001) compared to vehicle control. It was safe in the xenograft models as there was no significant body weight loss or other overt toxicities. In addition, histological analysis of major organs (liver, kidney, heart, bone marrow and intestine) of the mice receiving LS007 showed no drug related toxicities. These results support for development of LS007 towards the clinical trials for the treatment of TNBC and ER+ BC. Citation Format: Muhammed Hamidur Rahaman, Yinghui Zhang, Md Saiful Islam, Gary Heinemann, Abel Tesfaye Anshabo, Hugo Albrecht, Robert Milne, Shudong Wang. LS007, a potent and orally bioavailable CDK9 inhibitor, suppresses the growth of triple-negative and estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019 2019 Mar 29-Apr 3 Atlanta, GA. Philadelphia (PA): AACR Cancer Res 2019 (13 Suppl):Abstract nr 4427.
Targeting CDK9 for treatment of colorectal cancer
Publisher: Wiley
Date: 21-08-2019
Targeting CDK9: a promising therapeutic opportunity in prostate cancer
Publisher: Bioscientifica
Date: 12-2016
DOI: 10.1530/ERC-16-0299
Abstract: Cyclin-dependent kinase 9 (CDK9) is a key transcriptional regulator and a lucrative target for cancer treatment. Targeting CDK9 can effectively confine the hyperactivity of androgen receptor and the constitutive expression of anti-apoptotic proteins both being main causes of prostate cancer (PCa) development and progression. In castrate-resistant PCa, traditional therapies that only target androgen receptor (AR) have become obsolete due to reprograming in AR activity to make the cells independent of androgen. CDK9 inhibitors may provide a new and better therapeutic opportunity over traditional treatment options by targeting both androgen receptor activity and anti-apoptotic proteins, improving the chances of positive outcomes, especially in patients with the advanced disease. This review focuses on biological functions of CDK9, its involvement with AR and the potential for therapeutic opportunities in PCa treatment.
Dual inhibition of Mnk2 and FLT3 for potential treatment of acute myeloid leukaemia
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.EJMECH.2017.08.006
Abstract: The discovery of novel anti-AML therapeutic agents is urgently needed, but the complex heterogeneity of the disease has so far h ered the development of a curative treatment. FLT3 inhibitors have shown therapeutic potential in clinical trials but a monotherapy regimen has been associated with resistance mediated by the activation of parallel signalling circuitry, including MAPK and mTOR. Therefore, inhibiting a nexus of the two signalling pathways along with inhibition of FLT3 might be advantageous. Herein, we propose that a dual inhibition of FLT3 and Mnk would provide a better clinical option for AML patients compared to targeting FLT3 alone. Thus, a series of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines and 4-(indol-3-yl)-N-phenylpyrimidin-2-amines were prepared. Potent Mnk2 inhibitors, FLT3 inhibitors, and dual inhibitors of Mnk2 and FLT3 were identified and their anti-proliferative activities assessed against MV4-11 AML cell lines. Dual inhibition of FLT3 and Mnk2 caused the increased apoptotic cell death of MV4-11 cells compared to inhibition of FLT3 or Mnk2 alone.
ASSA: Fast identification of statistically significant interactions between long RNAs
Publisher: World Scientific Pub Co Pte Lt
Date: 02-2018
DOI: 10.1142/S0219720018400012
Abstract: The discovery of thousands of long noncoding RNAs (lncRNAs) in mammals raises a question about their functionality. It has been shown that some of them are involved in post-transcriptional regulation of other RNAs and form inter-molecular duplexes with their targets. Sequence alignment tools have been used for transcriptome-wide prediction of RNA–RNA interactions. However, such approaches have poor prediction accuracy since they ignore RNA’s secondary structure. Application of the thermodynamics-based algorithms to long transcripts is not computationally feasible on a large scale. Here, we describe a new computational pipeline ASSA that combines sequence alignment and thermodynamics-based tools for efficient prediction of RNA–RNA interactions between long transcripts. To measure the hybridization strength, the sum energy of all the putative duplexes is computed. The main novelty implemented in ASSA is the ability to quickly estimate the statistical significance of the observed interaction energies. Most of the functional hybridizations between long RNAs were classified as statistically significant. ASSA outperformed 11 other tools in terms of the Area Under the Curve on two out of four test sets. Additionally, our results emphasized a unique property of the [Formula: see text] repeats with respect to the RNA–RNA interactions in the human transcriptome. ASSA is available at rojects/assa/
Drifted catalytic properties of ss-lactamases due to unconstrained use of antibiotics
Publisher: Bangladesh Journals Online (JOL)
Date: 19-12-2011
Abstract: Context: Antibiotic resistance is an old problem with new face as the rate of infections due to multidrug resistant bacteria is increasing everyday and the number of new antibiotics to overwhelm the problem is becoming smaller. Major mechanism beneath this growing resistance is concomitant with the changes in ?-lactamases catalytic activity and its functional enhancement. Objectives: In ?-lactamases secreting clinical isolates at least 10% are extended-spectrum ?-lactamases (ESBL) that are not even treatable with ?-lactamases inhibitor like clavulanic acids. This implies that the catalytic domains of ?-lactamases have been mutated towards higher pathogenicity. The aim of the present study is to define the changes in ?-lactamases catalytic efficiency against ?-lactam antibiotics and its inhibitors. Materials and Methods: In this research work we have used multiple drug resistant (MDR) strains from surgical site of infections. A rapid method was used for specific detection of bacterial ?-lactamases that uses ?-lactam antibiotics as substrates. In this, the end products (open beta-lactam ring forms) generated after separately incubating substrates with ?-lactamases producing strains. Those end products of antibiotics were highly fluorescent after specific treatment and could be analyzed visually under long-wave UV l for efficiency. Results: ?-lactamases secreting strains are variably capable of defending ?-lactam antibiotics. Interestingly, one of the E. coli strain secretes ESBL, this means that the strain is resistant against clavulanic acid. However, the most fascinating fact of the finding is that ideally the ?-lactamases supposed to hydrolyze Penicillin by default but in our isolates, ?-lactamases are not able to hydrolyze penicillin instead they hydrolyze amoxicillin, a derivative which replaced clinical use of penicillin. In addition to that we have identified the presence of New Delhi Metalo- beta- lactamase in one of the clinical isolates. Conclusion: Rate of evolution in microbes is very high. Thus we presume that some of the amino acids in the functional domain of ?-lactamases have been changed respective to extinct use of penicillin whereas it is effective against clinically used other beta lactam antibiotics. DOI: 0.3329/jbs.v19i0.12999 J. bio-sci. 19 37-42, 2011
CDK12: a potential therapeutic target in cancer
Publisher: Elsevier BV
Date: 12-0040
Highly Potent, Selective, and Orally Bioavailable 4-Thiazol-N-(pyridin-2-yl)pyrimidin-2-amine Cyclin-Dependent Kinases 4 and 6 Inhibitors as Anticancer Drug Candidates: Design, Synthesis, and Evaluation
Publisher: American Chemical Society (ACS)
Date: 16-02-2017
DOI: 10.1021/ACS.JMEDCHEM.6B01670
Abstract: Cyclin D dependent kinases (CDK4 and CDK6) regulate entry into S phase of the cell cycle and are validated targets for anticancer drug discovery. Herein we detail the discovery of a novel series of 4-thiazol-N-(pyridin-2-yl)pyrimidin-2-amine derivatives as highly potent and selective inhibitors of CDK4 and CDK6. Medicinal chemistry optimization resulted in 83, an orally bioavailable inhibitor molecule with remarkable selectivity. Repeated oral administration of 83 caused marked inhibition of tumor growth in MV4-11 acute myeloid leukemia mouse xenografts without having a negative effect on body weight and showing any sign of clinical toxicity. The data merit 83 as a clinical development candidate.
Related Organisations
Moscow Institute Of Physics And Technology (State University)
Location: Russian Federation
University Of Copenhagen Biotech Research And Innovation Centre
Location: Denmark
Related Funding Activities
No related grants have been discovered for Muhammed Hamidur Rahaman.