KRAS is one of the most frequently mutated oncogenes in various cancers. KRAS G12D mutation is prevalent in 39% of pancreatic ductal adenocarcinoma (PDAC), 27% of colorectal cancer, 11% of non-small cell lung adenocarcinoma as well as in a subset of other solid tumors. KRAS G12V mutation is found in 31% of PDAC, 20% of colorectal cancer and 19% of non-small cell lung adenocarcinoma. KRASG12C mutations are found in 41% of non-small cell lung adenocarcinoma and 3-5% of colorectal cancers. Despite recent advances in small molecule KRAS inhibitors, a majority of KRAS alterations are not yet addressed. Further, in cases where inhibitors are available, resistance rapidly emerges. Eliminating all mutant KRAS using a targeted protein degradation approach may lead to superior efficacy relative to inhibiting the protein. We have identified a series of degraders through structure-based drug design and our Directed Neo-substrate Degrader (DNsD) approach, with very high co-operativity, potent pan-KRAS degradation activity and a desirable pharmacokinetic profile. The high co-operativity of pan-KRAS degraders was confirmed though Surface Plasmon Resonance (SPR) analysis. These degraders demonstrated significant degradation of KRAS in multiple KRAS mutant cell lines and showed mechanistic activity via the modulation of pERK levels leading to significant anti-proliferative activity. The KRAS degraders were found to be selective against HRAS and NRAS which was also confirmed using global proteomic analysis. Further, the development candidate molecule demonstrated significant and dose dependent tumor growth inhibition in multiple KRAS mutant xenograft models which was accompanied by sustained KRAS degradation. Notably, the development candidate compound has demonstrated excellent PK and tolerability in rodent and non-rodent tox species. IND enabling studies are ongoing to support clinical development. Dinesh Chikkanna, Madhu Aeluri, Leena Khare, Ravindra MV, Debajyoti Basak, Uday Bhat, Suraj T. Gore, Narmatha V, Shailesh V. Jadhav, K Y. Vasantha, Sivapriya Marappan, Megha Goyal, R N. Raghavendra, Amit A. Dhudashiya, Kiran Aithal, T Jagadeesh Kumar, D S. Suhas, K B. Charamanna, P Dharani, R Naveenkumar, Rahul B. Chavan , Randeep Bokalial, D S. Samiulla, Subhendu Mukherjee, Thomas Antony, Kavitha Nellore, Rajesh Eswarappa, Girish Chandrappa Daginakatte, Sanjeev Giri, Susanta Samajdar, Murali Ramachandra. Discovery and development of a highly co-operative and potent pan-KRAS degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7017.
The BAF (SWI/SNF) chromatin remodeling complex comprises of two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1), that affect the mobilization and positioning of nucleosomes on DNA and thereby regulate important cellular functions including transcription, DNA recombination, DNA repair and chromosome decatenation during mitosis. Genetic silencing studies have established that the oncogenic activity of tumors lacking SMARCA4 is primarily driven by SMARCA2-containing residual SWI/SNF complex. Thus, targeting SMARCA2 in a SMARCA4 mutant setting is synthetically lethal. Considering this well-established biological rationale, selective targeting of SMARCA2 could be a precision oncology opportunity to meet an unmet medical need. Here, we report the identification and development of highly selective SMARCA2 degrader with oral bioavailability that have demonstrated robust efficacy in SMARCA4 mutant CDX models. SMARCA2 selective degraders were identified by optimizing an assembly of SMARCA2/4 Bromodomain binders, degron connecting linkers and several ligands of specific E3 ligases. Design prioritizations were done using a proprietary ternary complex modelling algorithm, ALMOND (ALgorithm for MOdeling Neosubstrate Degraders). Prioritized designs were synthesized and profiled in multiple cellular assays to understand the mechanistic and functional readouts. Several compounds that potently and selectively degrade SMARCA2 were identified with a distinct phenotype in a panel of SMARCA4 mutant cell lines. ADME optimization led to development of compounds with encouraging oral bioavailability in rodent as well as non-rodent species. Global proteomics indicated highly selective SMARCA2 downregulation in a SMARCA2/4 proficient cell line. Further, the identified degrader demonstrated robust efficacy supported by SMARCA2 degradation in multiple SMARCA4-mutant CDX models, at well-tolerated doses. Repeat dose tolerability profile of the lead compound in non-rodent species is ongoing towards candidate nomination. Chandrasekhar Abbineni, Kiran Aithal, Bilash Kuila, Sandeep Vitthal Dukare, Prasath Kothandaraman, Arya Desai, Megha Goyal, Khaji Abdul Rawoof, Dhaytadak Bhagwan Mahadeo, Gopinath CH, T Jagadeesh Kumar, Charamanna KB, Rahul B. Chavan, Nandish C, Suraj Tgore, Leena Khare, DS Samiulla, Subhendu Mukherjee, Thomas Antony, Kavitha Nellore, Sanjeev Giri, Rajesh Eswarappa, Girish Daginakatte, Murali Ramachandra, Susanta Samajdar. Discovery of highly selective, potent and orally bio-available SMARCA2 degraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7024.
The BAF (SWI/SNF) chromatin remodeling complex comprises of two mutually exclusive ATPases, SMARCA2 (BRM) and SMARCA4 (BRG1), that affect the mobilization and positioning of nucleosomes on DNA and thereby regulates important cellular functions including transcription, DNA recombination, DNA repair and chromosome decatenation during mitosis. SMARCA4 is frequently overexpressed in several types of cancers. Overexpression has been linked to increased proliferation and survival, as well as aggressive tumors and poor prognosis. SMARCA4 knockdown in these tumors lead to inhibition of proliferation and increased sensitivity to known chemotherapeutic agents, supporting the validity of targeting SMARCA4. In addition, PTEN and SMARCA4 appear to share synthetic lethality relationship based on reported in vitro and in vivo knockdown studies. Considering this well-established biological rationale, selective degradation of SMARCA4 should offer significant clinical benefit in multiple disease settings. Here, we report first-in-class SMARCA4 selective degraders that demonstrate distinct cellular phenotype. As part of the initial design plan, selective SMARCA2/4 Bromodomain inhibitors and specific ligands of several E3 ligases were chosen to arrive at different degrader designs. Several linkers and different exit vectors were considered to construct a variety of hetero-bifunctional degrader molecules. Our proprietary ternary complex modeling algorithm, ALMOND4 (ALgorithm for MOdeling Neosubstrate Degraders) helped in prioritizing the designs. Shortlisted compounds were synthesized and profiled in multiple cellular assays to understand their potential to degrade SMARCA4 selectively. These compounds exhibited very potent anti-proliferative activity in cell lines of hematological and prostate cancer origin (e.g. MV-4-11, VCaP, etc.) whereas no significant potency is observed in SMARCA4 mutant cell lines. Identified compounds have shown selective degradation of SMARCA4 over SMARCA2 in multiple cell lines. Few potent SMARCA4 selective degraders were optimized for pharmacokinetic properties and further evaluation of tolerability and efficacy in rodents is in progress. Chandrasekhar Abbineni, Kiran Aithal, Bilash Kuila, Sandeep Vitthal Dukare, Arya Desai, Megha Goyal, Khaji Abdul Rawoof, Gauri Rahul Petkar, Gopinath CH, T Jagadeesh Kumar, Charamanna KB, Rahul B. Chavan, Nandish C, Suraj Tgore, Leena Khare, DS Samiulla, Subhendu Mukherjee, Thomas Antony, Kavitha Nellore, Sanjeev Giri, Rajesh Eswarappa, Girish Daginakatte, Susanta Samajdar, Murali Ramachandra. Identification of first-in-class paralog selective SMARCA4 degraders for treatment of hematological and prostate malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7019.
A pigmented bioactive molecule from Streptomyces kunmingensis BS19 was isolated, characterized, and evaluated for anti-infective, antiproliferative, and wound-healing properties. The yellow–red pigment produced from the strain BS19 showed promising activity against methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. Extracellular bioactive pigment from the strain BS19 was produced by agar surface fermentation and purified through bioassay guided preparative HPLC-based purification. Based on the results of UV, FT-IR, GC–MS, 1H NMR, and 13C NMR spectral analyses, the purified pigment was identified as a chromopeptide class of molecule with phenoxazinone chromophore. Its molecular weight was determined as the chemical formula C64H90N12O16 and molecular weight 1283 g/mol. It exhibited promising antimicrobial activity against Staphylococcus aureus (ATCC 1720) and antiproliferative activity against 14 types of human cancer cell lines. It showed good in vivo wound-healing activity in the rat model. The present study explored Streptomyces kunmingensis as a newly added source for the isolation of chromopeptide antibiotics for antimicrobial, wound-healing, and anticancer applications.
