Background: Relatively little is known about the genomic basis and evolution of wood- feeding in beetles. We undertook genome sequencing and annotation, gene expression assays, studies of plant cell ...wall degrading enzymes, and other functional and comparative studies of the Asian longhorned beetle, Anoplophora glabripennis, a globally significant invasive species capable of inflicting severe feeding damage on many important tree species. Complementary studies of genes encoding enzymes involved in digestion of woody plant tissues or detoxification of plant allelochemicals were undertaken with the genomes of 14 additional insects, including the newly sequenced emerald ash borer and bull-headed dung beetle. Results: The Asian longhorned beetle genome encodes a uniquely diverse arsenal of enzymes that can degrade the main polysaccharide networks in plant cell walls, detoxify plant allelochemicals, and otherwise facilitate feeding on woody plants. It has the metabolic plasticity needed to feed on diverse plant species, contributing to its highly invasive nature. Large expansions of chemosensory genes involved in the reception of pheromones and plant kairomones are consistent with the complexity of chemical cues it uses to find host plants and mates. Conclusions: Amplification and functional divergence of genes associated with specialized feeding on plants, including genes originally obtained via horizontal gene transfer from fungi and bacteria, contributed to the addition, expansion, and enhancement of the metabolic repertoire of the Asian longhorned beetle, certain other phytophagous beetles, and to a lesser degree, other phytophagous insects. Our results thus begin to establish a genomic basis for the evolutionary success of beetles on plants.
Abstract EP300 (or p300) acts as histone acetyltransferase (HAT) and transcriptional adapter or co-activator regulating transcription via chromatin remodeling. Both histone and non-histone proteins ...are acetylated by p300. In addition to HAT function, p300 has crotonyl-transferase activities, and that p300-catalyzed histone crotonylation directly stimulates transcription to a greater degree. p300 functions by scaffolding or as co-activator and enhancer of different transcription factors like HIF1a, BRCA-1, p53, NFκB, c-Myc, estrogen receptor (ER) and androgen receptor (AR) and other proteins such as PD-L1 and FOXP3. Selective targeting of p300 is expected to lead to therapeutic efficacy in CBP-mutant and p300-dependent malignancies with high degree of tolerability because of sparing of the other paralog CBP in normal cells. CBP mutant cancers comprise of several solid and hematological malignancies including 10% to 15% of non-small cell and small cell lung cancers harboring loss-of-function (LOF) aberrations. p300-dependent malignancies include prostate cancer, in which p300 plays a major role for androgen-dependent and -independent transactivation of the AR, MYCN-amplified neuroblastoma and ER+ breast cancers. Since the conventional CBP/p300 inhibitors do not discriminate between CBP and p300 proteins due to high sequence homology, we adopted a degrader approach, which has the potential to lead to paralog selectivity due to differentiated ternary complex formation. Herein we report best-in-class novel, potent and paralog selective p300 degraders with excellent selectivity over CBP and and other bromodomain containing proteins such as BRD4 by implementing molecular modeling, iterative medicinal chemistry and SAR based approaches. Synthetic lethality has been demonstrated while selectively degrading p300 in the cell lines having LOF mutation of another paralogue, CBP. Identified selective p300 degraders displayed excellent selectivity towards p300 degradation across tested cell lines and are orally bioavailable. Selective antiproliferative activity was observed in a panel of cell lines with CBP mutations or p300 dependency including AR+/ER+ cell lines along with the downregulation of target genes. In summary, we have identified highly selective degraders of p300 with desirable profile. Efforts are underway to advance them further towards nominating a development candidate. Citation Format: Saravanan Thiyagarajan, Chandrasekhar Abbineni, Krishna Chaitanya T, Achala Apte, Iram Khan Iqbal, Naveen Kumar R, Aravind A B, Avinash Kumar, Dabbeeru Madhu Babu, Shwetha Shwetha, Ankita Manna, Monalisha Mandal, Rituparna Panigrahi, Sivapriya Marappan, Suraj T Gore, Mohamad Fairus, Lim Yang Jin, Subhendu Mukherjee, Girish Daginakatte, Shekar Chelur, Kavitha Nellore, Murali Ramachandra, Susanta Samajdar. Paralogue selective p300 degraders induce synthetic lethality in pre-clinical models of CBP-deficient and p300-dependent malignancies abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3303.
Abstract
E1A binding protein (p300) and its paralog CREB binding protein (CBP or CREBBP) are ubiquitously expressed histone acetyl transferases (HAT). They act by scaffolding or as co-activator and ...enhancer of different transcription factors like HIF1a, BRCA-1, p53, c-Myc, PD-L1, Estrogen receptor (ER) and Androgen receptor (AR). CBP and p300 are multidomain proteins that harbour different functional units imperative for chromatin remodelling and transcription like Bromodomain (BD), Histone acetyl transferase (HAT) domain, KIX domain etc. These two closely related epigenetic modulators are known to play oncogenic role in a variety of cancers. Conventional CBP/p300 inhibitors targeting either BD, HAT or KIX domain do not discriminate between CBP and p300 proteins due to high homology. Because of the indiscriminate inhibition of both proteins, HAT domain inhibitors showed tolerability issues preventing their clinical advancement. In contrast, bromodomain inhibitors are better tolerated because they only block coactivation function at the transcription level without impacting the scaffolding or global histone acetylation function. They show less than desirable efficacy in various cancer models within very well tolerated doses. The implication of selective inhibition of either of these proteins in various cancer has been reported in the literature due to differential dependency on either of the paralogs. A synthetic lethal relationship between these paralogs in cancer set up has also been well established recently. However, none of the reported inhibitors of the various domains described above could selectively target CBP or p300 alone due to high sequence homology. Paralog selectivity in recent time has been proved to be possible with degrader approach due to differentiated ternary complex formation. Structure-guided modeling and iterative medicinal chemistry approaches were applied to identify paralog selective and potent first in class degraders with diverse linker length and linker composition. Identified compounds showed pronounced paralog selective degradation of target proteins and cellular effects in a panel of cell lines with loss of function mutation for either of the paralog proteins but not in wild type cells. The paralog selective lead degraders are currently being further optimized to identify development candidates. Selective degraders of CBP and p300 are expected to enhance efficacy of SOC drugs or immune checkpoint blockers by governing the acetylation and transcription of oncogenic factors and co-stimulatory molecules involved in tumor progression.
Citation Format: Chandrasekhar Abbineni, Saravanan Thiyagarajan, Krishna Chaitanya T, Achala Apte, Naveen Kumar R, Avinash Kumar, Dabbeeru Madhu Babu, Shwetha S, Aishwarya B Kamath, Monalisha Mandal, Rituparna Panigrahi, Sivapriya Marappan, Subhendu Mukherjee, Kavitha Nellore, Shekar Chelur, Murali Ramachandra, Susanta Samajdar. Discovery of potent and paralog selective PROTAC degraders of CBP or p300 proteins for the treatment of various cancers abstract. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A047.
We report a case of a 60-year old unmarried male who presented with multiple ulcers and foul smelling discharge from the groin since 4 months and multiple tense bullae over the trunk of 1 month ...duration. Groove sign was present. Investigations for lymphogranuloma venereum (LGV) and other sexually transmitted diseases were negative. Histopathology from the ulcer in the groin and growth in the penis revealed squamous cell carcinoma (SCC). Skin biopsy of bulla was diagnostic of bullous pemphigoid (BP). We report a rare case of SCC masquerading as LGV with BP occurring as a paraneoplastic phenomenon.
We report a case of a 60-year old unmarried male who presented with multiple ulcers and foul smelling discharge from the groin since 4 months and multiple tense bullae over the trunk of 1 month ...duration. Groove sign was present. Investigations for lymphogranuloma venereum (LGV) and other sexually transmitted diseases were negative. Histopathology from the ulcer in the groin and growth in the penis revealed squamous cell carcinoma (SCC). Skin biopsy of bulla was diagnostic of bullous pemphigoid (BP). We report a rare case of SCC masquerading as LGV with BP occurring as a paraneoplastic phenomenon.
We present a case report on anaesthetic management of a case of hemianomalous pulmonary venous connection with VSD, ASD for total intracardiac repair. A balanced anaesthetic technique was used with ...oxygen, isoflurane, fentanyl, midazolam, vecuronium. Patient was successfully operated under cardiopulmonary bypass with hypothermia.
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